CN113613637A

CN113613637A - Transdermal therapeutic system containing agomelatine

Info

Publication number: CN113613637A
Application number: CN202080022279.7A
Authority: CN
Inventors: P.莫尔; R.里切尔; R.埃弗勒; O.波奎因
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2019-12-20
Filing date: 2020-10-02
Publication date: 2021-11-05
Also published as: CA3162229A1; BR112022012111A2; EP4076382A1; EP4076382B1; WO2020260727A1; JP2023506538A

Abstract

The present invention relates to a Transdermal Therapeutic System (TTS) for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, this agomelatine TTS for use in a method of treatment, a method of treatment comprising the application of this agomelatine TTS, and a method of manufacturing this TTS.

Description

Transdermal therapeutic system containing agomelatine

Field of the invention

The invention relates to a Transdermal Therapeutic System (TTS) for the transdermal administration of agomelatine (agomelatine) to the systemic circulation, to a method for the production thereof, to a method for the treatment and to the use thereof.

Background

The active agent agomelatine (N- (2- (7-methoxy-1-naphthyl) ethyl) acetamide) is a melatoninergic antidepressant developed by Les laboratories server. The chemical structure is very similar to that of melatonin (melatonin).

Agomelatine, a melatoninergic agonist that stimulates the MT1 and MT2 receptors, mediates the synchronization of circadian rhythms, much like melatonin. However, in addition and unlike melatonin, agomelatine is also a 5-HT2B/5-HT2C antagonist, and blockade of the serotonergic 5HT2C receptor results in enhanced release of dopamine and norepinephrine in the prefrontal cortex. It has been observed that MT1/MT2 agonism and 5HT2C antagonism have an unexpected synergistic effect and it is speculated that this synergistic effect explains the antidepressant effect and the unique clinical profile of agomelatine.

Agomelatine has been used in Europe under the trade name Agomelatine

And

approved and indicated for the treatment of Major Depressive Disorder (MDD). The currently available form is a film tablet containing a dose of 25mg, which is prescribed with an initial dose taken one tablet at bedtime, if no improvement is seen, then the option of doubling the dose is employed. The agomelatine has the above effectsThe only mechanism used is the commercial antidepressant.

Oral agomelatine undergoes extensive first-pass and systemic metabolism primarily by the cytochrome CYP1a 2. Although agomelatine is well absorbed orally (>80%), but overall bioavailability is extremely low (less than 5%), with significant variability among individuals. Time to maximum plasma concentration and elimination half-life t_1/2Are all about 1 to 2 hours and at steady state, the distribution volume is 35 liters with 95% plasma protein binding.

The onset of action of agomelatine appears to be more rapid (typically within 1 week) when compared to other antidepressants, and the generally known major side effects of other antidepressants such as weight gain, sexual dysfunction, anticholinergic symptoms and cardiotoxicity appear to be reduced. However, agomelatine carries a risk of hepatotoxicity, whose mechanism has not yet been elucidated, which is manifested by an increased alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) value and, in few exceptional cases, the consequence is fatal or liver transplantation is necessary. Furthermore, liver damage was also reported to be associated with a large increase in agomelatine exposure, where AUC and c were observed for patients with moderate liver damage compared to healthy subjects_maxThe value is up to 140 times.

Servier and Novartis attempted to create sublingual dosage forms of agomelatine, presumably to avoid first pass metabolism and associated disadvantages as outlined above (low oral bioavailability and hepatotoxicity), resulting in placebo-controlled randomized studies with 1 and 2mg (Servier) or 0.5 and 1mg agomelatine sublingual tablets (Novartis). For the 2008/2009Servier test, no results were publicly available. In the Novartis study beginning in 2011/2011, the efficacy of the agomelatine sublingual tablet was not better than that of placebo and there was no clear dose-response relationship, although it was shown that at least liver toxicity was rare. One reason for this result appears to have been the significant irritation caused by agomelatine when applied to the oral mucosa. Thus, the FDA decides not to grant approval for a drug in the united states, despite the advantages over other actives in treating MDD.

Transdermal administration of agomelatine will not only avoid the disadvantages associated with first-pass metabolism and oral administration, but will also avoid the irritating sensation induced by sublingual tablets. Furthermore, the bioavailability of agomelatine transdermal therapeutic systems should be high and therefore, depending on whether an increase in systemic delivery of the active can actually be shown when compared to oral dosage forms, it would be possible to lower the dose, which would not only lead to an increase in cost efficiency but also solve dose related problems such as hepatotoxicity. Transdermal delivery of agomelatine has been explored, but it appears challenging to formulate a dosage form suitable for passive transdermal delivery of agomelatine.

Passive transport of the active agent from a Transdermal Therapeutic System (TTS) through the skin utilizes a driving force based on the concentration gradient between the concentration of the active agent in the transdermal system and on the outer surface of the skin and the concentration in the blood stream. Compared to TTS utilizing active transport such as iontophoresis or microporation, the passive transport is advantageous in view of the complexity and ease of application of the TTS. However, to create this driving force, a balance must be found between a sufficiently high drug concentration in the TTS and an excessive solubility of the drug in the active-containing layer, since the latter would be detrimental to a high skin permeation rate. Agomelatine is a poorly soluble drug and several different polymorphic forms of agomelatine are known. To prevent recrystallization of the drug after storage, which is undesirable as it can affect TTS performance due to the drug crystallizing in an unpredictable form and thus can lead to reduced shelf life, and also to achieve sufficiently high drug concentrations, the formulation must be such that the solubility of agomelatine is sufficiently high. This requirement must be balanced with adequate skin penetration of the drug.

Furthermore, because agomelatine is primarily used to resynchronize the circadian rhythm, the desired drug release profile is a rapid initial increase followed by only an overnight release, unlike the continuous and stable drug exposure sought for the treatment of chronic diseases throughout the day (and often achieved by TTS formulations).

Agomelatine TTS formulations have been proposed which contain isopropanol, but isopropanol is a volatile solvent, and therefore the composition of formulations containing isopropanol is expected to change over time due to evaporation of the solvent. The total delivered amount of the formulation also appears to be low. Other formulations relying on fatty acid based ionic liquids appear to have been explored, but the drug concentration of these formulations is extremely low, and therefore, it appears to be necessary to increase the layer thickness to a size where TTS manufacture would be impractical on a large/industrial scale.

To date, no commercial agomelatine TTS is available.

In summary, there is a great need for alternative agomelatine administration forms, overcoming the drawbacks of the oral as well as sublingual administration routes. As outlined above, TTS will be able to address these drawbacks.

Therefore, there is a need in the art for agomelatine TTS with sufficiently high skin penetration of the drug.

Objects and summary of the invention

It is an object of the present invention to provide an agomelatine TTS that overcomes the above mentioned drawbacks of current agomelatine administration.

It is therefore an object of the present invention to provide a TTS for transdermal administration of agomelatine which provides a permeation rate sufficient to achieve a therapeutically effective dose.

Another object of the present invention is to provide a TTS for transdermal administration of agomelatine which provides a drug release profile with a rapid initial increase and allows overnight application, for example suitable for administration shortly before bedtime and removal of the TTS in the morning.

Another object of the present invention is to provide a TTS for transdermal administration of agomelatine which has sufficient storage stability with respect to the stability of the active agent as well as the stability of the composition and/or the stability of the drug release profile, in order in particular to prevent (re) crystallization of the active.

It is another object of the present invention to provide a TTS for transdermal administration of agomelatine, wherein the hepatotoxicity and the inter-individual variability are reduced and the bioavailability is increased when compared to oral administration.

Another object of the present invention is to provide a TTS for transdermal administration of agomelatine which, in terms of size and thickness, meets the need for convenient application, provides good patient compliance, and/or is easy and cost-effective to manufacture.

These and other objects are achieved by the present invention which, according to one aspect, relates to a transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i) agomelatine;

ii) a hydrophobic polymer; and

iii) at least 1 wt% of a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinylacetate copolymer;

wherein

The hydrophobic polymer is selected from the group consisting of: polyisobutylene, styrene-isoprene-styrene block copolymers, silicone acrylic hybrid polymers, polysiloxane-based pressure sensitive adhesives, and any mixtures thereof.

According to another aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i) agomelatine; and

ii) a hydrophobic polymer;

wherein

The hydrophobic polymer is selected from the group consisting of: polyisobutylene, styrene-isoprene-styrene block copolymers, silicone acrylic hybrid polymers, polysiloxane-based pressure sensitive adhesives, and any mixtures thereof, and

the agomelatine-containing layer belongs to a microreservoir type.

According to certain embodiments of the invention, the transdermal therapeutic system of the present invention is used in a method of treatment, preferably in a method of treating major depression.

According to other embodiments, the present invention relates to a method of treatment, and in particular to a method of treatment of major depression, comprising applying the transdermal therapeutic system of the present invention to the skin of a human patient.

According to other embodiments, the present invention relates to the use of the transdermal therapeutic system according to the invention for the manufacture of a medicament for therapy, preferably for the treatment of major depression.

According to another aspect, the invention relates to a process for manufacturing an agomelatine-containing layer, comprising the following steps:

i) combining at least agomelatine, a hydrophobic polymer and a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinylacetate copolymer in a solvent to obtain a coating composition;

ii) applying the coating composition to a backing layer or release liner or any intermediate liner; and

iii) drying the applied coating composition to form the agomelatine-containing layer, wherein

The hydrophobic polymer is selected from the group consisting of: polyisobutylene, styrene-isoprene-styrene block copolymers, silicone acrylic hybrid polymers, and polysiloxane-based pressure sensitive adhesives.

According to certain embodiments, the invention also relates to a transdermal therapeutic system for the transdermal administration of agomelatine, obtainable by such a manufacturing process.

According to certain embodiments, the present invention also relates to a transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i)2 to 6 wt% agomelatine;

ii) a hydrophobic polymer;

iii)2 to 7 wt% polyvinylpyrrolidone; and

iv)2 to 7 wt% of a penetration enhancer selected from levulinic acid and polyglycol ether;

wherein

The hydrophobic polymer is selected from silicone-based pressure sensitive adhesives, and

wherein the agomelatine-containing layer has an areal weight of from 35 to 70g/m²Within the range of (1).

According to a further embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i)2 to 6 wt% agomelatine;

ii) a hydrophobic polymer; and

iii)7 to 15 wt% polyvinylpyrrolidone;

wherein

Within the meaning of the present invention, the term "transdermal therapeutic system" (TTS) refers to the system employed for the application of the active agent (agomelatine) to the systemic circulation by transdermal delivery and to the skin of the patient and comprises a therapeutically effective amount of agomelatine in a self-adhesive layer structure and optionally an integral single dosing unit comprising an additional adhesive cover layer on top of the agomelatine-containing self-adhesive layer structure. The self-adhesive layer structure may be located on a release liner (releasable protective layer), and thus the TTS may further comprise a release liner. Within the meaning of the present invention, the term "TTS" particularly refers to a system providing passive transdermal delivery, which excludes active transport as in methods comprising iontophoresis or microporation.

Within the meaning of the present invention, the term "agomelatine-containing self-adhesive layer structure" or "agomelatine-containing self-adhesive layer structure" containing a therapeutically effective amount of agomelatine refers to an active agent-containing structure that provides the release area of agomelatine during application. The adhesive cover layer adds to the overall dimensions of the TTS, but not to the release area. The self-adhesive agomelatine-containing layer structure comprises a backing layer and at least one agomelatine-containing layer.

Within the meaning of the present invention, the term "therapeutically effective amount" refers to the amount of active agent in the TTS which, if administered to a patient by the TTS, is sufficient to provide a blood level of agomelatine in a similar range (e.g. about 10% to about 1000%, as measured as AUC) when compared to the blood level obtained when 25mg oral agomelatine is administered once. TTS usually contain more active in the system than is actually provided to the skin and systemic circulation. This excess of active agent is generally necessary to provide a sufficient driving force to achieve passive transport from the TTS to the systemic circulation.

Within the meaning of the present invention, the terms "active", "active agent" and the like and the term "agomelatine" refer to agomelatine in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include, without limitation, agomelatine in its free dissociated or any associated form such as hydrate, solvate, etc., and agomelatine in the form of particles, which may be in micronized form, crystalline form, and in particular in one of its polymorphic forms, and/or in amorphous form; and any mixed form in any of the above mentioned forms or mixtures thereof. Agomelatine may be dissolved or dispersed, or partially dissolved and partially dispersed, when contained in a medium such as a solvent.

When it is mentioned that agomelatine is used in a particular form for the manufacture of TTS, this does not exclude the interaction between this form of agomelatine and the other ingredients of the self-adhesive layer structure containing agomelatine, so that the active is present in the final TTS in another form. This means that even if agomelatine is included in the free dissociated form, it may be present in the final TTS in the form of a hydrate or solvate, or if it is included in one of its polymorphic forms, it may be present in the final TTS in an amorphous form. Unless otherwise indicated, the amount of agomelatine in the self-adhesive layer structure relates in particular to the amount of agomelatine included in the TTS during the manufacture of the TTS and is calculated on the basis of agomelatine in free form, i.e. when agomelatine is included in an amount of 0.1mmol, the amount of agomelatine in the self-adhesive layer structure is considered to be 24.3mg (the molecular weight of agomelatine is 243g/mol), within the meaning of the present invention, whether agomelatine has been included in the TTS in its free form or in any associated form during the manufacture.

The agomelatine starting material included in the TTS during manufacture of the TTS may be in the form of particles. Agomelatine can be present in the self-adhesive layer structure, for example, in particulate and/or dissolved form.

Within the meaning of the present invention, the term "particles" refers to solid particulate materials comprising individual particles, the size of which is negligible compared to the material. In particular, the particles are solids, including plastic/deformable solids, including amorphous and crystalline materials.

Within the meaning of the present invention, the term "dispersion" refers to a step or a combination of steps in which the starting material (e.g. agomelatine) is not completely dissolved. In the sense of the present invention, the dispersion comprises a dissolution of a portion of the starting material (e.g. agomelatine particles), depending on the solubility of the starting material (e.g. the solubility of agomelatine in the coating composition).

There are two main types of TTS delivered using passive active agents, namely matrix-type TTS and depot-type TTS. In matrix TTS, the active agent is included in the matrix, whereas in reservoir TTS, the active agent is included in a liquid or semi-liquid reservoir. So-called microreservoir TTS is known in the art as a mixture between matrix-type TTS and reservoir-type TTS. The release of the active agent in a matrix TTS is controlled mainly by the matrix comprising the active agent itself. In contrast, reservoir TTS require a rate controlling membrane that controls the release of the active agent. Matrix-type TTS is advantageous because, compared to reservoir-type TTS, generally, a rate-determining membrane is not necessary and dose dumping does not occur due to membrane rupture. In summary, matrix-type Transdermal Therapeutic Systems (TTS) are less complex to manufacture and are easy and convenient to use by the patient. The microreservoir TTS also does not require a rate-determining membrane, but unlike the "classical" matrix TTS, the drug release profile is often characterized by a faster onset of the active and a higher availability, which is often advantageous.

Within the meaning of the present invention, a "matrix-type TTS" refers to a system or structure in which the active substance is homogeneously dissolved and/or dispersed in a polymeric carrier, i.e. a matrix, which forms a matrix layer together with the active agent and optionally with the remaining ingredients. In such systems, the matrix layer controls the release of the active agent from the TTS. The matrix TTS may also comprise a rate controlling membrane. The matrix-type TTS may in particular be in the form of a "drug in adhesive" -type TTS, which means a system in which the active substance is homogeneously dissolved and/or dispersed in the pressure-sensitive adhesive matrix.

TTS having a rate controlling membrane and a liquid or semi-liquid active agent containing reservoir is referred to by the term "reservoir-type TTS", wherein the release of the active agent from the TTS is controlled by the rate controlling membrane. Within the meaning of the present invention, a depot TTS is not to be understood as belonging to the matrix type.

Within the meaning of the present invention, a "microreservoir-type TTS" refers to a system or structure in which the active agent-containing layer is a two-phase layer having an internal active agent-containing phase in an external matrix phase. As used herein, the term "biphasic" refers to a system having two discernible, e.g., visually discernible regions, an outer phase and an inner phase, wherein the inner phase is in the form of discrete deposits within the outer phase. The deposit is for example a solid solution droplet. Visually discernible deposits can be identified through the use of a microscope.

Within the meaning of the present invention, the term "matrix layer" or "matrix-type layer" refers to any layer containing an active homogeneously dissolved and/or dispersed in a polymeric carrier. In general, the matrix layer is present as an active agent-containing layer in the matrix TTS. In addition to the reservoir layer and the rate controlling membrane, the reservoir-type TTS may also comprise an additional adhesive layer acting as a skin contact layer. In such a TTS of the reservoir type, the additional adhesive layer is often produced as an active agent-free layer. However, due to the concentration gradient, the active agent will migrate over time from the reservoir to the additional adhesive layer until equilibrium is reached. In such a TTS of the reservoir type, the additional adhesive layer therefore contains the active agent after a certain equilibration time and is regarded as an active agent-containing layer in the sense of the present invention.

The active agent-containing layer is the final cured layer obtained, for example, after coating and drying the solvent-containing coating composition. The active agent-containing layer can also be made by laminating two or more of the cured layers (e.g., dried layers) having the same composition to provide the desired areal weight. The active agent-containing layer may be self-adhesive (in the form of a pressure-sensitive adhesive layer), or the TTS may comprise an additional skin-contacting layer with a pressure-sensitive adhesive to provide sufficient adhesion. In particular, the active agent-containing layer is a pressure-sensitive adhesive layer.

Within the meaning of the present invention, the term "biphasic layer" means the final biphasic layer of the microreservoir TTS which is solidified after coating with the coating mixture, for example by drying the solvent-containing coating mixture or by cooling the hot-melt coating mixture. According to the invention, solvent-containing coating mixtures are preferred. The dual phase layer may also be made by laminating two or more layers of the same composition (e.g., dry layers) to provide the desired areal weight.

Within the meaning of the present invention, the term "dry biphasic layer" means a biphasic layer (solvent-based layer) obtained starting from a solvent-containing coating mixture after coating on a film and allowing the solvent to evaporate, and should be distinguished from a biphasic layer (hot-melt-based layer) obtained from a hot-melt coating mixture.

Within the meaning of the present invention, the term "pressure-sensitive adhesive" refers to a material which adheres, in particular under finger pressure, is permanently tacky, exerts a strong holding force, and should be removable from a smooth surface without leaving residues. The pressure sensitive adhesive layer is "self-adhesive" when in contact with the skin, i.e. provides adhesion to the skin so that no further assistance is generally required to achieve securement to the skin. The "self-adhesive" layer structure includes a pressure-sensitive adhesive layer for skin contact, which may be provided in the form of a pressure-sensitive adhesive active agent-containing layer or in the form of an additional layer, i.e., a pressure-sensitive adhesive skin-contacting layer. An adhesive cover layer may still be used to improve adhesion.

Within the meaning of the present invention, the term "skin contact layer" refers to a layer comprised in the TTS to be in direct contact with the skin of the patient during application. When the TTS comprises a skin contact layer, the other layers do not contact the skin and do not have to have self-adhesive properties. As outlined above, the skin contact layer may absorb a portion of the active agent over time, which may then be considered an active agent-containing layer. The release area is provided by the area of the active agent containing layer. The skin contact layer may be used to enhance adhesion. The dimensions of the additional skin contact layer and the active agent containing layer are generally coextensive and correspond to the area of release.

Within the meaning of the present invention, the term "area weight" means the amount in g/m of a particular layer, for example, an active agent-containing layer²Dry weight provided. Due to manufacturing variability, the area weight values are subject to a tolerance of ± 10%, preferably ± 7.5%.

If not otherwise indicated, "%" means% by weight.

Within the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. The polymer may have any configuration, such as a linear polymer, star polymer, comb polymer, brush polymer, in the case of a copolymer, any arrangement of monomers, such as alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to the skilled person. The polymer may for example have a molecular weight higher than 2,000, preferably higher than 5,000 and more preferably higher than 10,000 daltons (Dalton). Accordingly, compounds having a molecular weight of less than 2,000, preferably less than 5,000, or more preferably less than 10,000 daltons are generally referred to as oligomers.

Within the meaning of the present invention, the term "crosslinking agent" means a substance capable of crosslinking the functional groups contained within the polymer.

Within the meaning of the present invention, the term "adhesive cover layer" refers to a self-adhesive layer structure which is free of active agent and is larger in area than the active agent containing structure and provides additional area to adhere to the skin, but no active agent release area. It thus enhances the overall adhesive properties of the TTS. The adhesive cover layer comprises a backing layer and an adhesive layer.

Within the meaning of the present invention, the term "backing layer" refers to the layer supporting the agomelatine-containing layer or the backing forming the adhesive cover layer. At least one backing layer in the TTS, and typically the backing layer containing the agomelatine layer, is occlusive, i.e. substantially impermeable to the active agent contained in the layer during periods of storage and application, thus preventing loss or cross-contamination of the active, as required by regulatory requirements.

The TTS of the present invention can be characterized by certain parameters as measured in an in vitro skin penetration test.

The in vitro permeation test is carried out in Franz diffusion cells, using human or animal skin, and preferably using scalpels of edged skin with a thickness of 800 μm and an intact epidermis, and using a pH 5.5 or 7.4 phosphate buffer as receiving medium (32 ℃, with 0.1% azide salt), with or without addition of up to 40 vol% of an organic solvent such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400 so that the receiving medium may for example contain 60 vol% of pH 5.5 phosphate buffer, 30 vol% dipropylene glycol and 10 vol% acetonitrile.

When not otherwise indicated, in vitro permeation tests were performed on scalper-obtained skin of the skin with a thickness of 800 μm and intact epidermis, and with a phosphate buffer of pH 5.5 as receiving medium (32 ℃, with 0.1% azide salt). The amount of active permeated into the receiving medium was determined periodically by taking a certain sample volume, using an empirical HPLC method with a UV photometric detector. When the sample volume is taken, the receiving medium is completely or partially replaced by fresh medium, and the measured amount of permeated active relates to the amount permeated between the two nearest sampling points and not the total amount permeated so far.

Thus, within the meaning of the present invention, the parameter "penetration amount" is in μ g/cm²Provided, and relates to the amount of active permeated in a sampling interval at a certain elapsed time. For example, in an in vitro permeation test as described above, in which the amount of active permeated into the receiving medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, a sampling interval of active "permeation amount" of, for example, from 8 hours to 12 hours may be given and corresponds to the measurement result at 12 hours.

The amount of penetration may also be given in the form of a "cumulative amount of penetration" corresponding to the cumulative amount of active penetrated at a certain point in time. For example, in an in vitro permeation test as described above in which the amount of active permeated into the receiving medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "cumulative permeation amount" of active at 12 hours corresponds to the sum of the permeation amounts from 0 to 2 hours, 2 to 4 hours, 4 to 8 hours and 8 to 12 hours.

Within the meaning of the present invention, the parameter "skin permeation rate" with respect to a certain sampling interval at a certain elapsed time is in μ g/(cm)²h) Provided and measured in μ g/cm by an in vitro permeation test as described above in said sampling interval²The measured permeation was divided by the number of hours of the sampling interval. For example, in an in vitro penetration test as described above, in which the amount of active that penetrates into the receiving medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "skin penetration rate" at 12 hours is calculated as the amount of penetration in the sampling interval from 8 hours to 12 hours divided by 4 hours.

The "cumulative skin permeation rate" can be calculated from the corresponding cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in an in vitro penetration test as described above, in which the amount of active that penetrates into the receiving medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "cumulative skin penetration rate" at 12 hours is calculated as the cumulative penetration amount for 12 hours (see above) divided by 12 hours.

Within the meaning of the present invention, the above parameters permeation amount and skin permeation rate (as well as cumulative permeation amount and cumulative skin permeation rate) refer to the average values calculated from 3 ex vivo permeation test experiments.

The TTS of the present invention may also be characterized by certain parameters as measured in vivo clinical studies.

Within the meaning of the present invention, the term "administering" refers to applying a dosage form, i.e. TTS, to the skin of a patient, which dosage form is then maintained on the skin for a certain period of time.

In a typical continuous treatment for MDD, the frequency of drug administration is kept high enough to maintain a therapeutically effective plasma concentration. The interval between two dosage form administrations, also referred to as dosing interval, needs to be adapted accordingly. Within the meaning of the present invention, the term "dosing interval" refers to the period between two consecutive administrations of the TTS, i.e. the interval between two consecutive time points of applying the TTS to the skin of the patient. To maintain the plasma concentration at therapeutic levels, the TTS is typically maintained on the patient's skin for the entire dosing interval and is only removed at the end of the dosing interval, at which time a new TTS is applied to the skin. For example, if the dosing interval is 168 hours or 7 days, the TTS is applied to the skin of the patient and maintained on the skin for 168 hours or 7 days. After 168 hours or 7 days, the TTS was removed from the skin and a new TTS was applied. Thus, a 168 hour or 7 day dosing interval allows for a once-a-week TTS replacement mode in a full-day treatment.

For continuous treatment with agomelatine, the TTS will generally be administered once daily (24 hours between doses) and preferably at bedtime. TTS can be applied to the skin of a patient, particularly shortly before bedtime (e.g., 1-2 hours) to allow for delayed onset of the drug and is maintained on the skin for up to 24 hours. If the TTS is maintained on the skin for 24 hours, the TTS may be removed and a new TTS may be applied at the same time. Since it does not seem necessary for agomelatine to maintain plasma concentrations at therapeutic levels throughout the day, or may even be contraindicated for resynchronization of the circadian rhythm, it is possible to remove the TTS during the daytime so that the patient does not wear any TTS thereafter during the daytime. In an overnight application only, the TTS is maintained on the skin only during the night, for example for a period of between 4 and 12 hours, or between 6 and 10 hours, or during sleep depending on the length of the patient's sleep, and then removed in the morning.

Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory in which the experiment is carried out and is generally within 15 to 35 ℃, preferably about 18 to 25 ℃.

Within the meaning of the present invention, the term "patient" refers to a subject who has exhibited one or more specific symptoms indicative of a need for treatment, has been treated prophylactically or prophylactically with respect to a condition, or has been diagnosed with a condition to be treated.

The clinical study of the present invention refers to a study conducted under the international harmonization conference (ICH) in full compliance with clinical trials and all applicable local good clinical norms (GCP) and legislation.

Within the meaning of the present invention, the term "coating composition" refers to a composition comprising all the components of a drug layer in a solvent, which composition can be applied to a backing layer or release liner to form a drug-containing layer upon drying.

Within the meaning of the present invention, the term "dissolution" refers to the process of obtaining a solution that is clear and free of any particles as can be seen with the naked eye.

Within the meaning of the present invention, the term "solvent" refers to any liquid substance, which is preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, hexane, n-heptane, toluene and mixtures thereof.

Within the meaning of the present invention, and unless otherwise specified, the term "about" means an amount of ± 10% of the disclosed amount. In some embodiments, the term "about" means an amount of ± 5% of the disclosed amount. In some embodiments, the term "about" means an amount of ± 2% of the disclosed amount.

Drawings

Fig. 1a depicts the skin permeation rate of agomelatine for 0 to 24 hours for TTS prepared according to examples 1a, 1b and 1 c.

Fig. 1b depicts the agomelatine utilisation after 8 hours of the TTS prepared according to examples 1a, 1b and 1 c.

Fig. 1c depicts the agomelatine utilisation after 24 hours of the TTS prepared according to examples 1a, 1b and 1 c.

Fig. 2a depicts the skin permeation rate of agomelatine for 0 to 24 hours for TTS prepared according to examples 2a, 2b, 2c, 2d and 2 e.

Fig. 2b depicts the agomelatine utilisation after 8 hours for TTS prepared according to examples 2a, 2b, 2c, 2d and 2 e.

Fig. 2c depicts the agomelatine utilisation after 24 hours of the TTS prepared according to examples 2a, 2b, 2c, 2d and 2 e.

Fig. 3a depicts the skin permeation rate of agomelatine for 0 to 24 hours for TTS prepared according to examples 2e, 3a, 3b, 3c and 3 d.

Fig. 3b depicts the agomelatine utilisation after 8 hours for TTS prepared according to examples 2e, 3a, 3b, 3c and 3 d.

Fig. 3c depicts the agomelatine utilisation after 24 hours of the TTS prepared according to examples 2e, 3a, 3b, 3c and 3 d.

Fig. 3d depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 3 d.

Fig. 4a depicts the skin permeation rate of agomelatine for 0 to 24 hours for TTS prepared according to examples 4a, 4b, 4c, 4d and 4 e.

Fig. 4b depicts the agomelatine utilisation after 8 hours for TTS prepared according to examples 4a, 4b, 4c, 4d and 4 e.

Fig. 4c depicts the agomelatine utilisation after 24 hours of the TTS prepared according to examples 4a, 4b, 4c, 4d and 4 e.

Fig. 4d depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 4 c.

Fig. 5a depicts the skin permeation rate of agomelatine for 0 to 8 hours for TTS prepared according to examples 5a, 5b, 5c and 5 d.

Fig. 5b depicts the agomelatine utilisation after 8 hours of the TTS prepared according to examples 5a, 5b, 5c and 5 d.

Fig. 5c depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 5 b.

Fig. 5d depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 5 d.

Fig. 6a depicts the skin permeation rate of agomelatine for 0 to 12 hours for TTS prepared according to examples 3c, 6a, 6b, 6c and 6 d.

Fig. 6b depicts the agomelatine utilisation after 8 hours for TTS prepared according to examples 3c, 6a, 6b, 6c and 6 d.

Fig. 6c depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 6 a.

Fig. 6d depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 6 c.

Fig. 7a depicts the skin permeation rate of agomelatine for 0 to 24 hours for TTS prepared according to examples 7a, 7b, 7c, 7d and 3 d.

Fig. 7b depicts the agomelatine utilisation after 8 hours for TTS prepared according to examples 7a, 7b, 7c, 7d and 3 d.

Fig. 7c depicts the agomelatine utilisation after 24 hours for TTS prepared according to examples 7a, 7b, 7c, 7d and 3 d.

Fig. 8a depicts the skin permeation rate of agomelatine for 0 to 24 hours for TTS prepared according to examples 8a, 8b, 8c and 8 d.

Fig. 8b depicts the agomelatine utilisation after 8 hours for TTS prepared according to examples 8a, 8b, 8c and 8 d.

Fig. 8c depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 8 b.

Fig. 8d depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 8 d.

Fig. 8e depicts the sum of the possible degradation substances and the amount of agomelatine detected in the storage stability tests carried out at different time points at 25 ℃ and 60% RH, 30 ℃ and 75% RH and 40 ℃ and 75% RH for the TTS prepared according to example 8 b.

FIG. 8f depicts the adhesion and peel forces determined in storage stability tests carried out at different time points at 25 ℃ and 60% RH, 30 ℃ and 75% RH and 40 ℃ and 75% RH of the TTS prepared according to example 8 b.

Fig. 8g depicts the sum of the possible degradation substances and the amount of agomelatine detected in the storage stability tests carried out at different time points at 25 ℃ and 60% RH, 30 ℃ and 75% RH and 40 ℃ and 75% RH for the TTS prepared according to example 8 d.

FIG. 8h depicts the adhesion and peel forces determined in storage stability tests carried out at different time points at 25 ℃ and 60% RH, 30 ℃ and 75% RH and 40 ℃ and 75% RH of the TTS prepared according to example 8 d.

Fig. 9a depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 9 a.

Fig. 9b depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 9 b.

Fig. 9c depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 9 c.

Fig. 9d depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 9 d.

Fig. 9e depicts a micrograph of the agomelatine-containing layer of the TTS prepared according to example 9 e.

Detailed Description

TTS structure

The present invention relates to a transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing agomelatine.

Self-adhesive layer structure containing a therapeutically effective amount of agomelatine and comprising a) a backing layer and B) an agomelatine-containing layer comprising i) agomelatine and ii) a hydrophobic polymer.

Accordingly, a transdermal therapeutic system for the transdermal administration of agomelatine comprises a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer;

B) an agomelatine-containing layer comprising:

i) agomelatine; and

ii) a hydrophobic polymer.

In certain embodiments, the agomelatine-containing layer further comprises a crystallization inhibitor, or comprises at least 1 wt% crystallization inhibitor.

Thus, in certain embodiments of the invention, a transdermal therapeutic system for the transdermal administration of agomelatine comprises a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer;

B) an agomelatine-containing layer comprising:

i) agomelatine;

ii) a hydrophobic polymer; and

iii) at least 1 wt% of a crystallization inhibitor.

The backing layer is in particular substantially impermeable to agomelatine.

The TTS of the invention may in particular be a matrix-type TTS or a microreservoir-type TTS, and more preferably a microreservoir-type TTS.

In such a matrix or microreservoir TTS, a therapeutically effective amount of agomelatine is included in the agomelatine-containing layer. The self-adhesive layer structure in such a matrix-type or microreservoir-type TTS may comprise one or more further layers, such as a skin contact layer. In such other layers, the active agent may or may not be included. As outlined above, even if made as an active agent-free layer, the skin contact layer may comprise agomelatine after equilibration, which may then also be considered as an additional agomelatine-containing matrix type or microreservoir type layer. The other layer and the agomelatine-containing layer may comprise the same hydrophobic polymer or different polymers. Any agomelatine-containing layer and one or more other layers may be in direct contact with each other, or separated by a membrane such as a rate controlling membrane. If the agomelatine-containing layer is prepared by laminating two layers having substantially the same composition, the resulting bilayer will be considered as one layer.

In a TTS of the reservoir type, the active agent is included in a liquid or semi-liquid reservoir. The self-adhesive layer structure in such a TTS of reservoir type may comprise one or more further layers such as a skin contact layer. In such other layers, the active agent may or may not be included. As outlined above, even if manufactured as an active agent-free layer, the skin contact layer may comprise agomelatine after equilibration, which may then also be considered as an agomelatine-containing layer in the sense of the present invention. The reservoir-type TTS also includes a rate controlling membrane separating the reservoir and the skin contact layer.

Thus, in certain embodiments, the self-adhesive layer structure comprises an additional reservoir layer located between the backing layer and the agomelatine-containing layer, and another rate controlling membrane located between the additional reservoir layer and the agomelatine-containing layer.

In a particular embodiment, the self-adhesive layer structure of the invention comprises an additional skin contact layer. The additional skin contact layer is self-adhesive and provides adhesion between the self-adhesive layer structure and the patient's skin during application.

In such embodiments, the self-adhesive layer structure may or may not comprise a film between the agomelatine-containing layer and the additional skin contact layer, wherein the film is preferably a rate controlling film.

In another embodiment, the self-adhesive layer structure of the invention does not comprise an additional skin contact layer. Sufficient adhesion between the self-adhesive layer structure and the patient's skin during application is provided by other means, such as an agomelatine-containing layer and/or an adhesive layer. In particular, the self-adhesive layer structure may consist of a backing layer and an agomelatine-containing layer.

Thus, according to certain embodiments of the present invention, the TTS may further comprise an adhesive cover layer or not, and preferably not. This adhesive cover layer is in particular larger than the agomelatine-containing self-adhesive layer structure and adheres to it in order to enhance the adhesive properties of the overall transdermal therapeutic system. The adhesive cover layer further comprises a backing layer. The area of the adhesive cover layer adds to the overall size of the TTS, but not to the release area. The adhesive cover layer comprises a self-adhesive polymer or a self-adhesive polymer mixture selected from the group of acrylic polymers, polyisobutylene, styrene-isoprene-styrene copolymers, polysiloxanes and mixtures thereof, which may be the same or different from any (e.g. hydrophobic) polymer or polymer mixture included in the active agent-containing self-adhesive layer structure.

The self-adhesive layer structure of the invention is typically located on a detachable protective layer (release liner) from which it is removed immediately prior to application to the surface of the skin of a patient. Thus, the TTS may further comprise a release liner. TTS protected in this way is usually stored in seam-sealed pouches. The package may be child-resistant and/or senior friendly.

Agomelatine-containing layer

As outlined in more detail above, the TTS according to certain embodiments of the present invention comprises a self-adhesive layer structure comprising an agomelatine-containing layer.

In these embodiments, the agomelatine-containing layer comprises:

i) agomelatine; and

ii) a hydrophobic polymer.

As outlined above, the agomelatine-containing layer may further comprise a crystallization inhibitor, or at least 1 wt% crystallization inhibitor.

In some particular embodiments, the agomelatine-containing layer is of microreservoir type or of matrix type, and preferably of microreservoir type. In such embodiments, agomelatine may be completely dissolved, or may be in dispersed form.

As already indicated, the active agent-containing layer in a microreservoir-type TTS is a two-phase layer having an internal active agent-containing phase in an external matrix phase, the internal phase being in the form of discrete deposits within the external phase.

When the agomelatine-containing layer contains a crystallization inhibitor, it is presumed that agomelatine exists in a homogeneous form together with the crystallization inhibitor in the inner phase, and the hydrophobic polymer exists as a separate phase, thereby forming the outer phase of the two-phase layer.

Thus, in certain embodiments of the invention, the agomelatine-containing layer is a dry biphasic layer having

a) An external phase having a pressure-sensitive adhesive composition comprising a hydrophobic polymer, and

b) an internal phase having a composition comprising agomelatine,

wherein the inner phase forms dispersed deposits in the outer phase.

As already outlined, it is assumed that the crystallization inhibitor, if contained in the agomelatine-containing layer, is present together with the agomelatine within the droplets of the inner phase, thereby forming a homogeneous phase, which may be, for example, a viscous liquid or amorphous phase or a solid solution of so-called agomelatine dissolved in the crystallization inhibitor and optionally other excipients such as solubilizers. Thus, in such embodiments, the composition of the inner phase comprises a crystallization inhibitor and preferably the pressure sensitive adhesive composition of the outer phase comprises substantially no crystallization inhibitor, in particular the pressure sensitive adhesive composition of the outer phase may comprise less than or equal to 5 wt%, preferably less than or equal to 3 wt%, or more preferably less than or equal to 1 wt% crystallization inhibitor.

In another aspect, the hydrophobic polymer is believed to be present in the external phase. Thus, in these embodiments, the composition of the internal phase comprises substantially no hydrophobic polymer, and in particular, the composition of the internal phase comprises less than or equal to 5 wt%, preferably less than or equal to 3 wt%, or more preferably less than or equal to 1 wt% hydrophobic polymer.

As indicated by the term "microreservoir," the dispersed deposits have a micron size, i.e., in certain embodiments, the dispersed deposits have an average particle size of 0.1 to 100 μm, or 0.5 to 50 μm.

Microreservoir systems have the following advantages: a sufficient amount of active may be dissolved in the internal phase without having to increase the drug solubility of the actual adherent layer, i.e. the external phase, which may result in poor drug release. Without wishing to be bound by theory, it is assumed that this balance of a sufficient amount of active substance in the inner phase and a low solubility of the drug in the outer phase leads to a good permeation profile of the TTS of the invention involved. Such a system also has the advantage that (re) crystallization of the active can be prevented and associated limitations on storage stability.

Furthermore, in general, and irrespective of whether the agomelatine-containing layer is of microreservoir type, in a particular embodiment of the invention, the agomelatine-containing layer is free of agomelatine crystals.

Furthermore, the areal weight of the agomelatine-containing layer is a factor in determining the amount of active. A certain thickness is required to obtain a sufficient amount of active and it is also difficult to apply extremely thin layers, especially with sufficient accuracy. On the other hand, very thick layers are not only uncomfortable to wear and tend to separate from the skin, but are also difficult to manufacture and tend to result in continuous release of the active for up to 24 hours or more, which in the case of agomelatine is not the desired release profile. In summary, it is preferred that the agomelatine-containing layer has at least 25g/m²More preferably at least 35g/m²Or most preferably at least 40g/m²Or an areal weight of less than or equal to 150g/m²More preferably 120g/m or less²Or most preferably less than or equal to 90g/m²Or an areal weight of from 25 to 150g/m²More preferably 35 to 120g/m²Or most preferably from 40 to 90g/m²Area weight of (c).

Although the release area controls the effective dose and therefore requires a certain minimum size in terms of release area, if the release area is too large, the TTS will be large in size, which is uncomfortable to wear and leads to poor patient compliance. With this in mind, in certain embodiments of the invention, the transdermal therapeutic system has at least 1cm²Preferably at least 5cm²Or more preferably at least 10cm²Or has a release area of less than or equal to 100cm²Preferably less than or equal to 60cm²Or more preferably less than or equal to 50cm²Or has a release area of 1 to 100cm²Preferably 5 to 60cm²Or more preferably 10 to 50cm²The area of release of (a).

As also outlined above, and without wishing to be bound by theory, it is believed that a sufficient amount of active agent contained in the TTS is necessary to achieve certain advantageous features of the TTS of the present invention, such as good in vitro skin penetration. On the other hand, if the amount of active is too high, this may lead to undesirable storage stability problems such as recrystallization of the active, but also to potential skin irritation due to too high a drug concentration. The amount of agomelatine contained in the TTS can be controlled bi-directionally by adjusting the concentration and/or the areal weight of the agomelatine-containing layer. Details concerning area weight are summarized above. Regarding the concentration, the agomelatine-containing layer contains at least 0.5 wt% agomelatine, preferably at least 1 wt% agomelatine, and more preferably at least 1.5 wt% agomelatine, or the agomelatine-containing layer contains less than or equal to 8 wt% agomelatine, preferably less than or equal to 6 wt% agomelatine, and more preferably less than or equal to 5 wt% agomelatine, or the agomelatine-containing layer contains 0.5 to less than or equal to 8 wt% agomelatine, preferably 1 to less than or equal to 6 wt% agomelatine, and more preferably 1.5 to less than or equal to 5 wt% agomelatine.

Thus, in certain embodiments of the invention, the agomelatine-containing layer comprises at least 0.04mg/cm in terms of unit area of release²Preferably at least 0.06mg/cm²More preferably at least 0.08mg/cm²Or most preferably at least 0.1mg/cm²Agomelatine, or agomelatine-containing layer thereof, containing less than or equal to 0.4mg/cm²Preferably less than or equal to 0.3mg/cm²More preferably 0.25mg/cm or less²Or most preferably less than or equal to 0.2mg/cm²Agomelatine.

The amount of agomelatine contained in the transdermal therapeutic system is at least 0.5mg, preferably at least 1mg, or more preferably at least 2mg, or the amount of agomelatine contained in the transdermal therapeutic system is less than or equal to 15mg, preferably less than or equal to 10mg, or more preferably less than or equal to 8mg, or the amount of agomelatine contained in the transdermal therapeutic system is in the range of 0.5 to 15mg, or preferably 1 to 10mg, or more preferably 2 to 8mg, as far as the amount of active substance per TTS is concerned.

In certain embodiments of the invention, the agomelatine-containing layer is a pressure-sensitive adhesive layer.

As will be further appreciated in more detail below, in certain embodiments it is preferred that the coating composition used to prepare the agomelatine-containing layer utilizes ethanol as a solvent, rather than water. Thus, the transdermal therapeutic system of the present invention is preferably obtainable (and/or obtained) by drying an applied coating composition comprising agomelatine, a hydrophobic polymer, optionally a crystallization inhibitor, i.e. polyvinylpyrrolidone, and ethanol. It is also preferred that the transdermal therapeutic system of the present invention is obtainable (and/or obtained) by drying a coated coating composition substantially free of water, e.g. comprising less than 1 wt%, preferably less than 0.5 wt% or more preferably less than 0.1 wt% water.

In case of considering its stability with respect to the composition of the agomelatine-containing layer, it is preferred that the agomelatine-containing layer does not contain any volatile components which carry the risk of evaporation after storage and of changes in composition. Thus, in certain embodiments, the agomelatine-containing layer comprises substantially no volatile solvent. In this sense, the volatile solvent may be selected from the group consisting of C1 to C3 straight and branched chain alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof. In particular, the agomelatine-containing layer contains less than or equal to 5 wt%, preferably less than or equal to 3 wt% and more preferably less than or equal to 1 wt% of volatile solvents. In particular, the agomelatine-containing layer may be substantially free of isopropanol, for example containing less than or equal to 5 wt%, preferably less than or equal to 3 wt%, and more preferably less than or equal to 1 wt% isopropanol.

Since the solubility of agomelatine may be too high and also in view of the reduced tendency to form microreservoir-type layers, it is preferred that the agomelatine-containing layer contains only a limited amount of acrylic polymer. Thus, in certain embodiments, the agomelatine-containing layer does not comprise an acrylic polymer in an amount greater than 70 wt%, preferably not greater than 50 wt%, and more preferably not greater than 30 wt% relative to the agomelatine-containing layer.

Agomelatine

According to the invention, the self-adhesive layer structure contains agomelatine in a therapeutically effective amount and the self-adhesive layer structure comprises an agomelatine-containing layer.

Although the active agent agomelatine may be present in the TTS according to the invention in any form, i.e. in its free dissociated or any associated form such as hydrates, solvates and the like, as well as in particulate form which may be in one of micronized form, crystalline form, and in particular in its polymorphic form, and/or in amorphous form, as well as in any mixed form or mixtures thereof in any of the above-mentioned forms, and in particular in the agomelatine-containing layer, it is preferred that agomelatine is present in free dissociated form.

Furthermore, in certain embodiments, agomelatine is included in the agomelatine-containing layer in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, mixed form of any of the foregoing forms, or a mixture thereof.

In certain embodiments, the agomelatine-containing layer composition is obtainable (and/or obtained) by incorporating agomelatine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, mixed form of any of the foregoing forms, or a mixture thereof.

The agomelatine in the agomelatine-containing layer may be (completely) dissolved or the agomelatine-containing layer may contain agomelatine particles, preferably consisting of agomelatine in its free dissociated form, so that agomelatine is present in dispersed form. Needless to say, if agomelatine is present in dispersed form, the agomelatine-containing layer may still contain agomelatine also in dissolved form, depending on the solubility of the active in the agomelatine-containing layer (which is, for example, saturated or supersaturated).

In a preferred embodiment, the agomelatine is completely dissolved, e.g. at least 90 mol%, preferably at least 95 mol%, more preferably at least 98 mol% or most preferably at least 99 mol% of the agomelatine in the agomelatine-containing layer is present in dissolved form.

As outlined above, the amount of agomelatine in the TTS is believed to be important for a good release of the active and can be adjusted, for example, by the agomelatine concentration. Thus, in certain embodiments, the concentration of agomelatine in the agomelatine-containing layer is in the range of 0.5 to 8 wt%, preferably 1 to 6 wt% and more preferably 1.5 to 5 wt%, relative to the agomelatine-containing layer.

In certain embodiments, agomelatine has a purity of at least 95%, preferably at least 98%, and more preferably at least 99%, as determined by quantitative HPLC. Quantitative HPLC can be performed using reverse phase HPLC with UV detection. In particular, if the HPLC is performed in an isocratic manner, the following conditions may be used:

column: RP eighteen phase

XTerra RP 18100 mm x3.9mm; 3.5 μm or equivalent

Mobile phase: 0.06 molal KH₂PO₄Buffer/acetonitrile (60: 40; v: v); pH 2.5

Gradient: equal degree

Flow rate: 1.0ml

Sample introduction volume: 20 μ l

Column temperature: 23 deg.C

Wavelength: 229nm and 275nm

Operating time: 5 minutes

The TTS of the invention advantageously shows improved stability in terms of agomelatine content and agomelatine degradation.

Thus, in certain embodiments, the agomelatine-containing layer initially contains (i.e. shortly after manufacture, for example within one week) agomelatine in an amount of at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine included in the agomelatine-containing layer. The theoretical amount of agomelatine is calculated from the amount of agomelatine used in the coating composition and the (actual) areal weight of the coated and dried agomelatine-containing layers of the TTS tested.

The agomelatine-containing layer may also initially contain a total amount of agomelatine-related degradants of less than 0.5%, preferably less than 0.3%, more preferably less than 0.2%, and even more preferably less than 0.1%.

In certain other embodiments, the TTS of the invention are stable after storage, i.e. they can maintain the initial agomelatine content values, or exhibit low amounts of degradation products, as follows:

in one of such embodiments, the agomelatine-containing layer contains agomelatine in an amount of at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine included in the agomelatine-containing layer after having been stored at 25 ℃ and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

The agomelatine-containing layer may also contain a total amount of agomelatine-related degrading substances of less than 1.0%, preferably less than 0.5%, more preferably less than 0.2%, and even more preferably less than 0.1%, after having been stored at 25 ℃ and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

In one of such embodiments, the agomelatine-containing layer contains agomelatine in an amount of at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine included in the agomelatine-containing layer after having been stored at 30 ℃/75% RH for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

The agomelatine-containing layer may also contain a total amount of agomelatine-related degrading substances of less than 1.0%, preferably less than 0.5%, more preferably less than 0.2%, and even more preferably less than 0.1%, after having been stored at 30 ℃/75% RH for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

In one of such embodiments, the agomelatine-containing layer contains agomelatine in an amount of at least 95%, preferably at least 96%, more preferably at least 97%, and even more preferably at least 98% of the theoretical amount of agomelatine included in the agomelatine-containing layer after having been stored at 40 ℃/75% RH for at least 3 months, and preferably for at least 6 months.

The agomelatine-containing layer may also contain a total amount of agomelatine-related degrading substances of less than 1.0%, preferably less than 0.7%, more preferably less than 0.5%, and even more preferably less than 0.4%, after having been stored at 40 ℃/75% RH for at least 3 months, and preferably for at least 6 months.

The TTS of the invention are also advantageously stable after storage in terms of tack and removability of the agomelatine-containing layer from the release liner, i.e. they can maintain adhesion and peel force over time.

Thus, in certain embodiments, the adhesion of the agomelatine-containing layer decreases by less than 25%, preferably less than 10%, and more preferably less than 5% after having been stored at 25 ℃ and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

In certain embodiments, the adhesion of the agomelatine-containing layer decreases by less than 25%, preferably less than 10%, and more preferably less than 5% after having been stored at 30 ℃ and 75% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

The adhesion of the agomelatine-containing layer can also decrease by less than 20%, preferably less than 10%, and more preferably less than 3% after having been stored at 40 ℃/75% RH for at least 3 months, and preferably for at least 6 months.

In certain embodiments, the peel force of the agomelatine-containing layer increases by less than 150%, preferably less than 100%, and more preferably less than 30% after having been stored at 25 ℃ and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

In certain embodiments, the peel force of the agomelatine-containing layer increases by less than 250%, preferably less than 150%, and more preferably less than 100% after having been stored at 30 ℃ and 75% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

The peel force of the agomelatine-containing layer can also increase by less than 250%, preferably less than 100%, and more preferably less than 60% after having been stored at 40 ℃/75% RH for at least 3 months, and preferably for at least 6 months.

The method for determining the agomelatine content and the total amount of agomelatine-related degradation products, as well as the adhesion and peeling forces, is preferably carried out as described for examples 8b and 8 d.

Hydrophobic polymers

As outlined above, the TTS of the present invention comprises a self-adhesive layer structure comprising an agomelatine-containing layer comprising a hydrophobic polymer.

This hydrophobic polymer provides sufficient cohesion of the agomelatine-containing layer. According to certain embodiments, the hydrophobic polymer may also provide sufficient adhesion. In the described embodiments, and also generally, the hydrophobic polymer may be selected from pressure sensitive adhesive polymers.

In a preferred embodiment, the amount of hydrophobic polymer is at least 75 wt%, preferably at least 80 wt% and more preferably at least 75 wt% and/or the amount of hydrophobic polymer is less than or equal to 98 wt%, preferably less than or equal to 94 wt% and more preferably less than or equal to 90 wt% relative to the agomelatine-containing layer, and in particular the amount of hydrophobic polymer is in the range of 75 to 98 wt%, preferably 80 to 94 wt% and more preferably 85 to 90 wt%.

Polymers suitable as hydrophobic polymers of the present invention are selected from the group consisting of: polyisobutylene, styrene-isoprene-styrene block copolymers, silicone acrylic hybrid polymers, polysiloxane-based pressure sensitive adhesives, and any mixtures thereof.

The hydrophobic polymer is present in the agomelatine-containing layer, but may also be contained in an optional adhesive cover layer.

Hydrophobic polymers are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure sensitive adhesives is typically between 30% and 80%.

Suitable hydrophobic polymers of the invention may be, for example, Oppanol, under the trade name^TM(polyisobutylene), JSR-SIS (styrene-isoprene-styrene copolymer), SilAc Hybrid PSA (silicone acrylic Hybrid polymer), or BIO-PSA (polysiloxane-based pressure sensitive adhesive) are commercially available.

In a preferred embodiment, the hydrophobic polymer is a silicone-based pressure sensitive adhesive.

Polysiloxane-based pressure-sensitive adhesives may also be referred to as silicone-based pressure-sensitive adhesives, or silicone pressure-sensitive adhesives. They are advantageous in terms of availability of the active and overall release profile.

These silicone-based pressure sensitive adhesives provide suitable tack and provide quick adhesion to a variety of skin types including wet skin, suitable adhesive and cohesive properties, long-lasting adhesion to skin, high flexibility, moisture permeability, and compatibility with many actives and film substrates. It is possible to provide them with sufficient amine resistance, and therefore, the stability in the presence of amines is enhanced. The pressure-sensitive adhesives are based on the resin-in-polymer concept, in which polysiloxane-based pressure-sensitive adhesives are prepared by condensation reactions of silanol-terminated polydimethylsiloxanes with silica resins (also known as silicate resins), in which the residual silanol functions are additionally terminated with trimethylsiloxy groups for amine stability. The silanol-terminated polydimethylsiloxane content promotes the viscous component of the viscoelastic properties and affects the wetting and spreading properties of the adhesive. The resin acts as a tackifying and reinforcing agent and participates in the elastic component. The right balance between silanol terminated polydimethylsiloxane and resin provides the right adhesion properties.

In view of the above, silicone-based pressure-sensitive adhesives are generally obtainable by polycondensation of silanol-terminated polydimethylsiloxanes with silicate resins. In other words, in a preferred embodiment, the polysiloxane-based pressure sensitive adhesive is a soluble silicate resin condensed with silanol-terminated polydimethylsiloxane. Amine-compatible silicone-based polymers, and in particular, amine-compatible silicone-based pressure sensitive adhesives, are obtainable by reacting a silicone-based polymer, in particular a silicone-based pressure sensitive adhesive, with a trimethylsilyl group (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer. Thus, the residual silanol functions are at least partially, preferably mostly or completely, blocked by trimethylsiloxy groups. Thus, in certain embodiments, the polysiloxane-based pressure sensitive adhesive is a soluble silicate resin condensed with a silanol-terminated polydimethylsiloxane, wherein those silanol groups of the polydimethylsiloxane that are not attached to the soluble silicate resin are free silanol groups, or are trimethylsilylated.

As indicated above, the viscosity of the silicone-based polymer may be varied by the resin to polymer ratio, i.e. the ratio of silanol-terminated polydimethylsiloxane to silicate resin, which is preferably in the range of 70:30 to 50:50, preferably 65:35 to 55: 45. The tack will increase as the amount of polydimethylsiloxane relative to the resin increases. The high viscosity silicone-based polymer preferably has a 55:45 resin to polymer ratio, the medium viscosity silicone-based polymer preferably has a 60:40 resin to polymer ratio, and the low viscosity silicone-based polymer preferably has a 65:35 resin to polymer ratio. In a preferred embodiment, the polysiloxane-based pressure sensitive adhesive is a soluble silicate resin condensed with silanol terminated polydimethylsiloxane having 65:35, 60:40 or 55:45 of the resin withThe polymer ratio. The high viscosity silicone-based polymer preferably has about 5x10 at 0.01rad/s and 30 ℃⁶Poise complex viscosity, a medium viscosity silicone-based polymer preferably has about 5x10 at 0.01rad/s and 30 ℃⁷Poise complex viscosity, and a low viscosity silicone-based polymer preferably has about 5x10 at 0.01rad/s and 30 ℃⁸Complex viscosity of poise. The high viscosity amine compatible silicone based polymer preferably has about 5x10 at 0.01rad/s and 30 ℃⁶Poise complex viscosity, medium viscosity amine compatible silicone based polymers preferably have about 5x10 at 0.01rad/s and 30 ℃⁸Poise complex viscosity, and low viscosity amine compatible silicone based polymers preferably have about 5x10 at 0.01rad/s and 30 ℃⁹Complex viscosity of poise.

Examples of commercially available silicone-based PSA compositions include the standard BIO-PSA series (7-4400, 7-4500, and 7-4600 series), the amine-compatible (end-capped) BIO-PSA series (7-4100, 7-4200, and 7-4300 series), and the soft skin adhesive series (7-9800), manufactured by Dow Corning and commonly supplied in n-heptane or ethyl acetate. For example, BIO-PSA 7-4201 is characterized by a solution viscosity of 450 mPas at 25 ℃ and about 60% solids in heptane and a complex viscosity of 1X10 at 0.01rad/s at 30 ℃⁸Poise. BIO-PSA7-4301 has a solution viscosity of 500 mPas at 25 ℃ and about 60% solids content in heptane and has a viscosity of 5X10 at 0.01rad/s at 30 ℃⁶Complex viscosity of poise.

Polysiloxane-based pressure sensitive adhesives are supplied and used in solvents such as n-heptane, ethyl acetate or other volatile silicone fluids. The solids content of the silicone-based pressure-sensitive adhesive in the solvent is generally between 60 and 85%, preferably between 70 and 80%, or between 60 and 75%. The skilled person will appreciate that the solids content can be varied by adding an appropriate amount of solvent.

Silicone-based pressure sensitive adhesives available, for example, from Dow Corning are available according to the following procedure:

such silicone-based pressure sensitive adhesives are available from Dow Corning, for example under the trade name BIO-PSA 7-4401, BIO-PSA-7-4501 or BIO-PSA 7-4601, in the solvent n-heptane (indicated by the code "01"); or BIO-PSA 7-4402, BIO-PSA 7-4502 and BIO 7-4602, under the trade names BIO-PSA 7-4402, in the solvent ethyl acetate (indicated by the code "02"). Typical solids content in the solvent is in the range of 60 to 75%. The code "44" indicates a 65:35 resin to polymer ratio that yields low tack, the code "45" indicates a 60:40 resin to polymer ratio that yields medium tack, and the code "46" indicates a 55:45 resin to polymer ratio that yields high tack.

Amine compatible silicone based pressure sensitive adhesives such as those available from Dow Corning can be obtained according to the following procedure:

such amine compatible silicone based pressure sensitive adhesives are available from Dow Corning, for example under the trade designation BIO-PSA 7-4101, BIO-PSA-7-4201 or BIO-PSA7-4301, provided in the solvent n-heptane (indicated by code "01"); or BIO-PSA 7-4102, BIO-PSA 7-4202 and BIO 7-4302, under the trade names BIO-PSA 7-4202, in ethyl acetate (indicated by the code "02"). Typical solids content in the solvent is in the range of 60 to 75%. The code "41" indicates a 65:35 resin to polymer ratio that yields low tack, the code "42" indicates a 60:40 resin to polymer ratio that yields medium tack, and the code "43" indicates a 55:45 resin to polymer ratio that yields high tack.

In a certain embodiment, the silicone-based pressure sensitive adhesive of the present invention is characterized by a solution viscosity of greater than about 150mPa · s, or about 200mPa · s to about 700mPa · s, at 25 ℃ and 60% solids in n-heptane, preferably as measured using a Brookfield RVT viscometer equipped with a spindle 5 at 50rpmS. These silicone-based pressure sensitive adhesives are further characterized by a complex viscosity of less than about 1x10 at 0.01rad/s at 30 ℃⁹Poise or about 1x10⁵To about 9x10⁸Poise. Furthermore, in certain embodiments, the polysiloxane-based pressure sensitive adhesive is characterized by a solution viscosity of greater than about 350mPa · s, or from about 400mPa · s to about 1500mPa · s, at 25 ℃ and 60% solids in ethyl acetate, preferably as measured using a Brookfield RVT viscometer equipped with a rotor number 5 at 50rpm, or by a complex viscosity of about 1x10 mPa · s at 0.01rad/s at 30 ℃⁵To about 1x10⁷Poise or about 5x10⁶Poise.

In another embodiment, the hydrophobic polymer is polyisobutylene.

Suitable polyisobutenes according to the invention are available under the trade name

And (4) obtaining. A combination of high molecular weight polyisobutylene (B100/B80) and low molecular weight polyisobutylene (B10, B11, B12, B13) may be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene are in the range of 100:1 to 1:100, in particular 95:5 to 40:60, preferably 90:10 to 80:20 or 60:40 to 20:80, and preferably 50:50 to 30: 70. A preferred example of a polyisobutylene combination is B10/B100 in a ratio of 85/15, or in a ratio of 40/60.

B100 has a viscosity-average molecular weight M of 1,110,000_vAnd a weight average molecular weight M of 1,550,000_wAnd an average molecular weight distribution M of 2.9_w/M_n。

B10 has a viscosity-average molecular weight M of 40,000_vAnd a weight average molecular weight M of 53,000_wAnd an average molecular weight distribution M of 3.2_w/M_n. In certain embodiments, polybutene may be added to polyisobutylene. The solids content of the polyisobutene in the solvent is generally 30And 50%, preferably between 35 and 40%. The skilled person will appreciate that the solids content can be varied by adding an appropriate amount of solvent.

In another embodiment, the hydrophobic polymer is a styrene-isoprene-styrene block copolymer.

The hydrophobic polymer may also be a silicone acrylic hybrid polymer.

Silicone acrylic hybrid pressure sensitive adhesives are commonly supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure sensitive adhesives is typically between 30% and 80%. The skilled person will appreciate that the solids content can be varied by adding an appropriate amount of solvent.

Preferably, the weight ratio of silicone to acrylate in the silicone acrylic hybrid pressure sensitive adhesive is 5:95 to 95:5, or 20:80 to 80:20, more preferably 40:60 to 60:40, and most preferably the ratio of silicone to acrylate is about 50: 50.

Commercially available suitable silicone acrylic hybrid pressure sensitive adhesives include PSA series 7-6100 and 7-6300(7-610X and 7-630X; X ═ 1 based on n-heptane/X ═ 2 based on ethyl acetate) manufactured by Dow Corning and supplied in n-heptane or ethyl acetate. For example, a 7-6102 silicone acrylic hybrid PSA having a silicone/acrylate ratio of 50/50 is characterized by a solution viscosity of 2,500cP at 25 ℃ and about 50% solids content in ethyl acetate, and a complex viscosity of 1.0e7 poise at 0.1rad/s at 30 ℃. A 7-6302 silicone acrylic hybrid PSA with a silicone/acrylate ratio of 50/50 has a solution viscosity of 1,500cP at 25 ℃ and about 50% solids content in ethyl acetate, and a complex viscosity of 4.0e6 poise at 0.1rad/s at 30 ℃.

The arrangement of the silicone phase and the acrylic phase providing the silicone or acrylic continuous outer phase and the corresponding discontinuous inner phase is different depending on the solvent in which the silicone acrylic hybrid pressure sensitive adhesive is supplied. If the silicone acrylic hybrid pressure sensitive adhesive is provided in n-heptane, the composition contains a continuous silicone outer phase and a discontinuous acrylic inner phase. If the silicone acrylic hybrid pressure sensitive adhesive is provided in ethyl acetate, the composition contains a continuous acrylic outer phase and a discontinuous silicone inner phase. After evaporation of the solvent in which the silicone acrylic hybrid pressure sensitive adhesive is provided, the phase arrangement of the resulting pressure sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of any substance that can induce reversal of the alignment in the silicone acrylic hybrid pressure sensitive adhesive composition, a pressure sensitive adhesive layer prepared from a silicone acrylic hybrid pressure sensitive adhesive in n-heptane provides a continuous silicone outer phase and a discontinuous acrylic inner phase, and a pressure sensitive adhesive layer prepared from a silicone acrylic hybrid pressure sensitive adhesive in ethyl acetate provides a continuous acrylic outer phase and a discontinuous silicone inner phase. The phase alignment of the compositions can be determined, for example, in a peel force test with a pressure sensitive adhesive film or layer prepared from the silicone acrylic hybrid PSA composition attached to a siliconized release liner. If the siliconized release liner cannot or can only be removed laboriously from the pressure sensitive adhesive film (laminated to the backing film) due to the closure of both silicone surfaces, the pressure sensitive adhesive film contains a continuous silicone external phase. The encapsulation results from the adhesion of two silicone layers containing similar surface energies. Silicone adhesives show good spreading on the siliconized liner and therefore can create good adhesion to the liner. If the siliconized release liner is readily removable, the pressure sensitive adhesive film contains a continuous acrylic outer phase. Acrylic adhesives do not have good spreading due to different surface energies and therefore have low or little adhesion to the siliconized pad.

According to a preferred embodiment of the present invention, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure sensitive adhesive obtainable from a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups. It is to be understood that the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups may comprise only acrylate functional groups, only methacrylate functional groups, or both acrylate and methacrylate functional groups.

According to certain embodiments of the present invention, a silicone acrylic hybrid pressure sensitive adhesive comprises the reaction product of: (a) a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone acrylic hybrid pressure sensitive adhesive is the product of a chemical reaction between these reactants ((a), (b), and (c)). In particular, silicone acrylic hybrid pressure sensitive adhesives comprise the reaction product of: (a) a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) (meth) acrylate monomers, and (c) an initiator (i.e., in the presence of the initiator). That is, the silicone acrylic hybrid pressure sensitive adhesive includes the product of a chemical reaction between these reactants ((a), (b), and (c)).

(a) The reaction product of the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) ethylenically unsaturated monomer, and (c) initiator may contain a continuous external silicone phase and a discontinuous internal acrylic phase, or the reaction product of (a), (b), and (c) may contain a continuous external acrylic phase and a discontinuous internal silicone phase.

According to a certain embodiment of the invention, the silicone acrylic hybrid polymer comprises the reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinking and covalently bound to the silicone polymer and/or the silicone resin.

According to some other embodiment of the invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, wherein the silicone resin is present as each SiO_4/2Corresponding to 0.1 to 0.9R₃SiO_1/2The molar ratio of the units containing triorganosiloxy units R₃SiO_1/2(wherein R is an organic group) and a tetrafunctional siloxy unit SiO_4/2。

The acrylic polymer may comprise at least an alkoxysilyl functional monomer, a polysiloxane-containing monomer, a halosilyl functional monomer, or an alkoxy halosilyl functional monomer. Preferably, the acrylic polymer is prepared from an alkoxysilyl functional monomer selected from the group consisting of trialkoxysilyl (meth) acrylates, dialkoxyalkylsilyl (meth) acrylates, and mixtures thereof, or contains end-capped alkoxysilyl functional groups. The alkoxysilyl functional group may preferably be selected from the group consisting of: trimethoxysilyl, dimethoxymethylsilyl, triethoxymethylsilyl, diethoxymethylsilyl and mixtures thereof.

The acrylic polymer may also be prepared from a mixture comprising polysiloxane-containing monomers, preferably from a mixture comprising polydimethylsiloxane mono (meth) acrylate.

According to one embodiment of the invention, the silicone acrylic hybrid polymer may be prepared by: a) reacting a silicone polymer with a silicone resin to form a resulting product, b) reacting said resulting product of a) with an acrylic polymer containing reactive functional groups, wherein the components are reacted in an organic solvent.

According to one embodiment of the invention, the silicone acrylic hybrid polymer may be prepared by: a) reacting a silicone resin with an acrylic polymer containing reactive functional groups to form a resulting product, b) reacting said resulting product of a) with a silicone polymer, wherein the components are reacted in an organic solvent.

According to one embodiment of the invention, the silicone acrylic hybrid polymer may be prepared by: a) reacting a silicone polymer with an acrylic polymer containing reactive functional groups to form a resulting product, b) reacting said resulting product of a) with a silicone resin, wherein the components are reacted in an organic solvent.

Other suitable acrylic polymers, silicone resins and silicone polymers that can be used to chemically react silicone polymers, silicone resins and acrylic polymers together to provide a silicone acrylic hybrid polymer according to the previous paragraph are described in detail in WO 2010/124187.

Crystallization inhibitors and solubilizers

As outlined above, according to certain aspects and embodiments of the present invention, the agomelatine-containing layer comprises a crystallization inhibitor.

Within the meaning of the present invention, a "crystallization inhibitor" is any substance capable of preventing recrystallization of the active agent agomelatine in the TTS, and in particular in the agomelatine-containing layer of the invention. The skilled person is aware of suitable crystallization inhibitors.

To achieve the above mentioned effect of preventing recrystallization, but also to achieve a favorable effect on the permeation profile (see also below), a certain amount of crystallization inhibitor is required. On the other hand, if incorporated in high amounts, the permeation rate may be adversely affected due to too high solubility of the drug. Therefore, the agomelatine-containing layer preferably contains at least 1 wt% of a crystallization inhibitor. In a preferred embodiment, the agomelatine-containing layer comprises at least 1.5 wt%, preferably at least 2.5 wt%, more preferably at least 4 wt% and most preferably at least 5 wt% of such crystallization inhibitor, and in another aspect, equal to or less than 30 wt%, preferably equal to or less than 25 wt%, more preferably equal to or less than 20 wt% and most preferably equal to or less than 15 wt% of crystallization inhibitor, e.g. the agomelatine-containing layer may comprise 1.5 to 30 wt%, preferably 2.5 to 25 wt%, more preferably 4 to 20 wt% and most preferably 5 to 15 wt% of crystallization inhibitor.

Of particular interest as crystallization inhibitors are polymers with enhanced water absorption capacity, since higher water and/or moisture absorption helps maintain/improve the adhesive properties of the agomelatine-containing layer, and since said substances are believed to promote good skin penetration characteristics of the microreservoir system. That is, without wishing to be bound by any theory, it is believed that in the microreservoir system, the crystallization inhibitor present in the internal phase with the active agent has a higher affinity for water than for the active agent, so that skin water absorbed during application of the TTS to the skin of the patient displaces the dissolved active agent. The displaced active molecules experience a high driving force to achieve diffusion out of the TTS to the skin and into the skin.

Thus, in certain embodiments, the agomelatine-containing layer comprises a crystallization inhibitor selected from polymers that provide improved water and/or moisture absorption to the agomelatine-containing layer. Such polymers are well known in the art. Among these polymers, polyvinylpyrrolidone and polyethylene are particularly suitable and preferredPyrrolidone-polyvinyl acetate copolymer. The polyvinylpyrrolidone-polyvinylacetate copolymer may be supplied, for example, under the trade name BASF

VA64 is commercially available.

In certain embodiments, the crystallization inhibitor is selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinyl acetate copolymer. Preferably, the crystallization inhibitor is polyvinylpyrrolidone, and in particular, the crystallization inhibitor is selected from soluble polyvinylpyrrolidone.

The term "soluble polyvinylpyrrolidone" refers to a polyvinylpyrrolidone that can be more than 10% soluble in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, dichloromethane, 2-pyrrolidone,

polyethylene glycol

400, 1,2 propanediol, 1,4 butanediol, glycerol, triethanolamine, propionic acid, and acetic acid, also known as povidone. Examples of commercially available polyvinylpyrrolidones include those provided by BASF

12PF、

17PF、

25、

30 and

90F, or povidone K90F. Of different grades

Determined as K reflecting the average molecular weight of the polyvinylpyrrolidone grade.

12PF is characterized by a K value range of 10.2 to 13.8, corresponding to a nominal K value of 12.

17PF is characterized by a K value range of 15.3 to 18.4, corresponding to a nominal K value of 17.

25 is characterized by having a K value range of 22.5 to 27.0, corresponding to a nominal K value of 25,

30 are characterized by a K value range of 27.0 to 32.4, corresponding to a nominal K value of 30.

90F is characterized by a K value range of 81.0 to 97.2, corresponding to a nominal K value of 90. Preference is given to

The grade is

12PF、

30 and

90F. For all grades and types of polyvinylpyrrolidone it is preferred that the amount of peroxide is within certain limits, in particular the amount of peroxide is equal to or less than 500ppm, more preferably equal to or less than 150ppm and most preferably equal to or less than 100 ppm.

Within the meaning of the present invention, the term "K value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the respective theories of the european pharmacopoeia (ph. eur.) and USP about "povidone".

Thus, in certain embodiments, the crystallization inhibitor is selected from polyvinylpyrrolidone having a K value within a range selected from the group of ranges consisting of

9 to 15, and preferably 10.2 to 13.8,

15 to 20, and preferably 15.3 to 18.4,

20 to 27, and preferably 22.5 to 27.0,

27 to 35, and preferably 27.0 to 32.4, and

75 to 110, and preferably 81.0 to 97.2,

or any mixture thereof, and more preferably polyvinylpyrrolidone having a K value in the range of 27.0 to 32.4 or 81.0 to 97.2 and any mixture thereof, and most preferably polyvinylpyrrolidone having a K value in the range of 81.0 to 97.2.

In certain embodiments of the invention, the agomelatine-containing layer comprises a solubilizer.

Within the meaning of the present invention, the term "solubilising agent" means any substance capable of substantially increasing the solubility of agomelatine in the agomelatine-containing layer, for example by at least 1 percentage point (in terms of the amount of agomelatine in wt% in the agomelatine-containing layer) per 10 wt%, preferably per 5 wt%, more preferably per 1 wt%, and most preferably per 0.5 wt% of solubilising agent added to the agomelatine-containing layer.

In certain preferred embodiments, the solubilizing agent is selected from the group consisting of: dipropylene glycol; lauryl lactate; mixtures of propylene glycol monoesters and propylene glycol diesters of fatty acids, which mixtures are commercially available, for example, under the trade name Capryol, which is propylene glycol monocaprylate (form II), i.e. having>90% of monoester and<mixture of propylene glycol monoester and propylene glycol diester of fatty acids in a proportion of 10% diester, the fatty acids consisting mainly of caprylic acid (Capryol, available from Gattefoss é)^TM90 commercially available); levulinic acid; polyglycol ethers, in particular polyglycol fatty alcohol ethers (such as may be mentioned)

That is commercially availableThese) can be, for example

L4 commercially available polyethylene glycol dodecyl ether having an average molecular weight Mn of about 362; and diethylene glycol monoethyl ether (may be

Commercially available).

A certain minimum amount of solubilizer is advantageous because it will help prevent recrystallization of the active agent in the agomelatine-containing layer. On the other hand, if the amount of solubilizer is too high, the cohesion of the agomelatine-containing layer will be impaired, and therefore, a balance must be found. In view of these factors, in a certain preferred embodiment, the agomelatine-containing layer comprises at least 1.5 wt%, preferably at least 2.5 wt%, more preferably at least 4 wt% and most preferably at least 5 wt% of a solubilizing agent, and in another aspect, equal to or less than 30 wt%, preferably equal to or less than 25 wt%, more preferably equal to or less than 20 wt% and most preferably equal to or less than 15 wt% of a solubilizing agent, for example the agomelatine-containing layer may comprise 1.5 to 30 wt%, preferably 2.5 to 25 wt%, more preferably 4 to 20 wt% and most preferably 5 to 15 wt% of a solubilizing agent. In another embodiment, the agomelatine-containing layer does not comprise a solubilizing agent selected from the group consisting of: dipropylene glycol, lauryl lactate, mixtures of propylene glycol mono-and diesters of fatty acids, levulinic acid, polyethylene glycol ether, and diethylene glycol monoethyl ether.

Furthermore, the crystallization inhibitor and the solubilizer can complement each other in terms of the advantageous effect of preventing recrystallization of agomelatine. Thus, in certain embodiments, and in particular when the crystallization inhibitor is present in a sufficient amount, the agomelatine-containing layer does not comprise a solubilizing agent selected from the group consisting of: dipropylene glycol, lauryl lactate, mixtures of propylene glycol monoesters and propylene glycol diesters of fatty acids, levulinic acid, and polyethylene glycol ethers. Furthermore, preferably, the total amount of crystallization inhibitor and solubilizer present in the agomelatine-containing layer is at least 2.5 wt%, preferably at least 3.5 wt%, more preferably at least 4 wt%, and most preferably at least 5 wt%, and/or equal to or less than 30 wt%, preferably equal to or less than 25 wt%, more preferably equal to or less than 20 wt%, and most preferably equal to or less than 15 wt%, for example 1.5 to 30 wt%, preferably 2.5 to 25 wt%, more preferably 4 to 20 wt%, and most preferably 5 to 15 wt%.

Finally, the amount of crystallization inhibitor and/or solubilizer required to effectively prevent the recrystallization of agomelatine also depends on the amount of agomelatine present in the agomelatine-containing layer. Therefore, the ratio of the total amount of the crystallization inhibitor and the solubilizer present in the agomelatine-containing layer to the amount of agomelatine present in the agomelatine-containing layer is preferably at least 1:2, more preferably at least 1:1, and most preferably at least 2: 1. In the absence of a solubilizer, this total amount will refer to the amount of crystallization inhibitor.

Other additives

The agomelatine-containing layer of the TTS of the invention may comprise further excipients or additives selected from the group consisting of: cross-linking agents, other solubilizers, fillers, viscosity-increasing agents, plasticizers, stabilizers, emollients, skin-care substances, permeation enhancers, i.e. substances which influence the barrier properties of the stratum corneum in the sense of increasing the permeability of the active agent, pH regulators and preservatives.

Particularly preferred additives are stabilizers. The additives may be present in the agomelatine-containing layer in an amount of 0.001 to 15 wt% of each additive, relative to the agomelatine-containing layer. In a certain embodiment, the total amount of all additives is 0.001 to 25 wt% with respect to the agomelatine-containing layer. Hereinafter, when ranges are given for the amounts of particular additives, such ranges refer to the amount of each individual additive.

It should be noted that in pharmaceutical preparations, the formulation components are classified according to their physicochemical and physiological properties and according to their functions. This means in particular that substances or compounds belonging to one class are not excluded from belonging to another class of formulation components. For example, a certain polymer may be a crystallization inhibitor, but also a tackifier. Some substances may be, for example, typical emollients, but at the same time act as penetration enhancers. The skilled person will be able to determine on the basis of his general knowledge the class or classes of ingredients of a formulation to which a substance or compound belongs. In the following, details regarding excipients and additives are provided, however, the details should not be construed as being exclusive. Other substances not explicitly listed in the present description may also be used according to the invention and in the sense of the present invention, the use of substances and/or compounds explicitly listed for one formulation component category as another formulation component is not excluded.

The cross-linking agent may be selected from the group consisting of: aluminum and titanium crosslinking agents such as aluminum acetylacetonate, titanium acetylacetonate or polybutyl titanate. The amount of the crosslinking agent may be in the range of 0.005 to 1 wt%, and preferably 0.01 to 0.1 wt%, relative to the agomelatine-containing layer. The agomelatine-containing layer may also comprise a self-crosslinking polymer, i.e. a polymer comprising crosslinking functional groups such as glycidyl groups which react upon heating. According to another particular embodiment, the agomelatine-containing layer comprises a cross-linking agent as above and a self-crosslinking polymer.

The agomelatine-containing layer may contain, in addition to the one or more solubilising agents mentioned previously, other solubilising agents. Preferred other solubilizing agents include, for example, glycerol, polyglycerol esters, propylene glycol esters and polyoxyethylene esters of medium and/or long chain fatty acids, such as glycerol monolinoleate, medium chain glycerol esters and medium chain triglycerides; nonionic solubilizers prepared by reacting castor oil with ethylene oxide and any mixture thereof which may also contain a fatty acid or fatty alcohol; cellulose and methylcellulose and their derivatives such as hydroxypropyl cellulose and hydroxypropyl methylcellulose acetate succinate; various cyclodextrins and their derivatives; nonionic triblock copolymers with a central polyoxypropylene hydrophobic chain flanked by two hydrophilic chains of polyoxyethylene, known as poloxamers (poloxamers); graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, also abbreviated as PVAc-PVCap-PEG, and known as PVAc

And purified grade of natural castor oil, polyethylene glycol 400, polyoxyethylene sorbitanSugar alcohol monooleates (such as polysorbate 80) or propylene glycol; and insoluble/crosslinked polyvinylpyrrolidones, also known as crospovidone, such as

CL、

CL-M and

CL-SF。

however, in addition, the penetration enhancers mentioned below may act as other solubilizing agents.

Fillers such as silica gel, titanium dioxide and zinc oxide can be used in conjunction with the polymer to affect certain physical parameters, such as cohesive and cohesive strength, in a desired manner.

In case the agomelatine-containing layer is required to have self-adhesive properties and a hydrophobic polymer is chosen which does not provide sufficient self-adhesive properties, a tackifier is added. The tackifier may be selected from the group consisting of triglycerides, polyethylene glycols, dipropylene glycols, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethyl polysiloxanes and polybutenes, and mixtures thereof. In certain embodiments, the agomelatine-containing layer comprises an adhesion promoter in an amount of 5 to 15% relative to the agomelatine-containing layer.

In certain embodiments, the agomelatine-containing layer comprises a stabilizer selected from the group consisting of: sodium metabisulphite, ascorbic acid and its ester derivatives, butylated hydroxytoluene, tocopherols and their ester derivatives such as tocopheryl acetate and tocopheryl linoleate, preferably selected from tocopherol and its ester derivatives and ascorbic acid and its ester derivatives, in particular ascorbyl esters of fatty acids such as ascorbyl palmitate and alpha-tocopherol. When the agomelatine-containing layer contains a stabilizer, the amount of the stabilizer is 0.001 to 2 wt% relative to the agomelatine-containing layer.

In one embodiment, the agomelatine-containing layer further comprises a softener/plasticizer. Exemplary softeners/plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, and polyethylene glycols.

In certain embodiments, the agomelatine-containing layer comprises a permeation enhancer selected from: octanoic acid, glycerol, 2, 5-dimethylisosorbide ether, dimethylethyleneurea, N-diethyl-m-toluamide, polyethylene glycol, propylene glycol monocaprylate, 2-methoxy-4- (prop-2-en-1-yl) phenol, lactic acid, and laurocapram (laurocapram).

In certain other embodiments, the agomelatine-containing layer does not comprise a permeation enhancer selected from: diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lactic acid, dimethyl ethylene urea and dimethyl propylene urea.

The agomelatine-containing layer of the invention may contain a pH controlling agent. Preferably, the pH modifier is selected from the group consisting of amine derivatives, inorganic base derivatives, polymers having basic and acidic functional groups, respectively.

Release feature

The TTS of the invention is designed for the transdermal administration of a certain amount of agomelatine to the systemic circulation, in particular during the night hours.

The administration of the TTS of the invention generally and preferably consists of: applying the transdermal therapeutic system to the skin of a human patient, and maintaining the transdermal therapeutic system on the skin for at least 2 hours, preferably at least 4 hours, and more preferably at least 6 hours, and/or less than or equal to 24 hours, preferably less than or equal to 18 hours, and more preferably less than or equal to 14 hours, and/or from 2 to 24 hours, preferably from 4 to 18 hours, and more preferably from 6 to 14 hours.

In a particular embodiment of the invention, the TTS of the invention as described above provides the following agomelatine skin penetration rates as measured in Franz diffusion cells with skin obtained with a dermatome

At 2 hours, 0.5. mu.g/cm²-hr to 15. mu.g/cm²-hr，

At 4 hours, 1. mu.g/cm²-hr to 20. mu.g/cm²-hr，

At 8 hours, 2. mu.g/cm²-hr to 25. mu.g/cm²-hr, and

at 16 hours, 1. mu.g/cm²-hr to 15. mu.g/cm²-hr。

In certain embodiments, the transdermal therapeutic system of the present invention provides the following cumulative permeation amounts of agomelatine at 8 hours as measured in human skin obtained with a dermatome in a Franz diffusion cell: at least 0.01mg/cm²Preferably at least 0.015mg/cm²And more preferably at least 0.02mg/cm²And/or less than or equal to 0.2mg/cm²Preferably less than or equal to 0.15mg/cm²And more preferably less than or equal to 0.1mg/cm²And/or 0.01mg/cm²To 0.2mg/cm²Preferably 0.015mg/cm²To 0.15mg/cm²And more preferably 0.02mg/cm²To 0.1mg/cm²。

In certain embodiments, the transdermal therapeutic system of the present invention provides the following agomelatine utilization after 8 hours as measured on human skin obtained with a dermatome in a Franz diffusion cell: at least 10%, preferably at least 15% and more preferably at least 20%.

Therapeutic method/medical use

According to a particular aspect of the invention, the TTS of the invention is used in a method of treatment, and in particular in a method of treatment of a human patient. According to another aspect, the invention relates to a method of treatment, wherein the transdermal therapeutic system of the invention is applied to the skin, in particular to the skin of a human patient. In another aspect, the invention relates to the use of the transdermal therapeutic system according to the invention for the manufacture of a medicament for performing a therapy, preferably for treating a human patient.

Most patients suffering from classical mood disorders (major depression, the depressed phase of bipolar disorder, or generalized anxiety disorder) show a disruption in the sleep-wake cycle and sleep architecture in greater than 80%. As a feature, difficulty falling asleep (increased sleep latency) followed by intermittent sleep leads to significant daytime drowsiness that further impairs their ability to function properly in daily life, creating a vicious circle. With respect to depression, although there are no specific treatment guidelines, the available options are generally themselves based on the premise that depression and sleep disorders share a two-way relationship, and thus, successful treatment of one condition will benefit the other condition reciprocally.

In recent years, it has become increasingly clear that circadian rhythm disruptions-locking core physiological functions such as body temperature and blood pressure, but also locking extremely complex "body clock" disorders and dysfunctions of neurotransmitter response to the time of day-are major factors in major depressive disorders that will justify therapeutic attention. Dysfunctions of the association between the suprachiasmatic nucleus, the pineal gland and the neurohormone melatonin which it produces have been shown to be the main cause of these phenomena. Melatonin has been advocated (and sold) in great numbers as a "non-photic circadian rhythm resynchronization agent" to treat jet lag syndrome and shift-work-related insomnia, and many studies have been published on the antidepressant and anxiolytic effects of melatonin. Because of the low oral bioavailability of melatonin, synthetic melatonin receptor agonists have been explored; among them, agomelatine is the best known.

Although agomelatine is approved for the treatment of depression, other indications have been proposed such as bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia and OCD.

Thus, in certain embodiments, the TTS of the present invention is preferably used in a method of treating major depression. Also, in certain other embodiments, the present invention relates to a method of treating major depression, wherein the transdermal therapeutic system of the present invention is applied to the skin, in particular to the skin of a human patient. In other embodiments, the invention relates to the use of the transdermal therapeutic system of the invention for the manufacture of a medicament for the treatment of major depression.

Treatment of depression, or major depression also known as major depressive disorder, may include treatment of various conditions in depressed/MDD patients, such as major depressive episode, anxiety symptoms, sleep-wake cycle disorders, daytime sleepiness, and insomnia (most MDD patients, i.e., more than 80% suffer from depression with insomnia). In other embodiments, treatment may also generally involve treatment of bipolar disorder, generalized anxiety disorder, smith-magenis syndrome, periventricular leukomalacia, or OCD.

As outlined above, transdermal delivery avoids the first-pass effect, and therefore, unlike oral agomelatine dosage forms, the TTS of the present invention has a lower risk of hepatotoxicity. Thus, there is no limitation with respect to the group of patients to be treated. Thus, treatment includes treating human patients with or without liver damage, including those with at least mild or at least moderate liver damage.

Furthermore, in a certain embodiment, the treatment with the transdermal therapeutic system of the present invention provides a reduction of at least one agomelatine-related side effect with respect to an equivalent oral dose of agomelatine. As outlined above, in certain particular embodiments, this agomelatine-related side effect is hepatotoxicity. Agomelatine relative to an equivalent oral dose should be understood as a comparison in clinical studies of the occurrence and intensity of side effects when using transdermal agomelatine and oral agomelatine at doses that result in substantially the same plasma exposure of agomelatine. The occurrence of at least one agomelatine-related side effect may be reduced by at least about 30%, preferably at least about 40%, more preferably at least about 70%, and most preferably at least about 80% relative to an equivalent oral dose of agomelatine, and/or the intensity of at least one agomelatine-related side effect may be reduced relative to an equivalent oral dose of agomelatine. The intensity of the side effect can be determined, for example, by classifying the side effect on a scale indicating "mild", "moderate" or "severe" intensity, and the decrease in intensity can be quantified by comparing the median intensities.

In any of the treatments outlined for the above aspects and embodiments, the transdermal therapeutic system is preferably applied to and maintained on the skin of the human patient for at least 2 hours, preferably at least 4 hours, and more preferably at least 6 hours, and/or less than or equal to 24 hours, preferably less than or equal to 18 hours, and more preferably less than or equal to 14 hours, and/or from 2 to 24 hours, preferably from 4 to 18 hours, and more preferably from 6 to 14 hours.

In another embodiment, the TTS of the invention can also be used in a method for reducing at least one agomelatine-related side effect in a patient, relative to an equivalent oral dose of agomelatine.

The invention also relates to a method for reducing at least one agomelatine-related side effect in a patient treated with oral agomelatine therapy, said method comprising

a) Stopping oral agomelatine therapy; and

b) administering the transdermal therapeutic system of the present invention to the skin of said patient, wherein said transdermal therapeutic system provides a reduction of at least one agomelatine-related side effect relative to an equivalent oral dose of agomelatine.

In this way, the transdermal therapeutic system can deliver an amount of agomelatine equivalent to the amount of agomelatine originally provided by oral agomelatine therapy.

Manufacturing method

The invention also relates to a method for producing an agomelatine-containing layer for use in a transdermal therapeutic system, and to a corresponding self-adhesive layer structure and a corresponding TTS comprising said agomelatine-containing layer.

According to one aspect of the invention, the process for manufacturing an agomelatine-containing layer for use in a transdermal therapeutic system comprises the following steps:

iii) drying the applied coating composition to form the agomelatine-containing layer.

According to another aspect of the invention, the process for manufacturing an agomelatine-containing layer for use in a transdermal therapeutic system comprises the following steps:

i) combining at least agomelatine and a hydrophobic polymer in a solvent to obtain a coating composition;

iii) drying the applied coating composition to form a microreservoir-type agomelatine-containing layer.

In this method, the hydrophobic polymer is selected from the group consisting of: polyisobutylene, styrene-isoprene-styrene block copolymers, silicone acrylic hybrid polymers, and polysiloxane-based pressure sensitive adhesives.

In this manufacturing process, preferably, in step i), agomelatine is dissolved or dispersed, and more preferably dissolved, to obtain a coating composition.

It is preferred not to use water, since agomelatine is poorly soluble in water and will therefore be at risk of recrystallization.

Thus, in the above described process, the solvent may be selected from alcoholic solvents, in particular from methanol, ethanol, isopropanol and mixtures thereof, and may be selected from non-alcoholic solvents, in particular from ethyl acetate, hexane, n-heptane, petroleum ether, toluene and mixtures thereof. Preferably, the solvent comprises an alcoholic solvent selected from methanol, ethanol, isopropanol and mixtures thereof, and more preferably, the solvent comprises, or consists of, ethanol.

Furthermore, the solvent comprises substantially no water, e.g. the solvent comprises less than 1 wt%, preferably less than 0.5 wt%, and more preferably less than 0.1 wt% water.

Preferred for the hydrophobic polymer containing agomelatine layers, crystallization inhibitors and other ingredients are as outlined above. Thus, in some embodiments, step i) consists of combining in a solvent at least agomelatine, a hydrophobic polymer, polyvinylpyrrolidone and a solubilizer selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of propylene glycol mono-and diesters of fatty acids, levulinic acid, polyethylene glycol ether and diethylene glycol monoethyl ether to obtain the coating composition. Furthermore, in step i), agomelatine may be combined in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, mixed form of any of the foregoing forms or a mixture thereof.

In step iii), the drying is preferably carried out at room temperature and/or at a temperature of from 40 to 90 ℃, more preferably from 50 to 70 ℃ in one or more cycles.

The self-adhesive layer structure comprising the agomelatine-containing layer and the corresponding TTS can be manufactured using the process outlined above, using further manufacturing steps as known to the skilled person, such as lamination with a backing layer to obtain the self-adhesive layer structure, and stamping out the individual TTS and the packaging, for example by sealing in a pouch made from primary packaging material. The further steps preferably result in a self-adhesive layer structure or TTS as described in the preceding chapters.

The invention also relates in particular to agomelatine-containing layers obtainable and/or obtained by the process described above, as well as to self-adhesive layer structures and transdermal therapeutic systems.

Examples

The present invention will now be described more fully with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as limiting the invention. The values provided in the examples with respect to the amount or area weight of the ingredients in the composition may vary slightly due to manufacturing variability.

Examples 1A to 1C

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 1a to 1c are summarized in table 1.1 below. The formulations are based on weight percent, as also indicated in table 1.1.

TABLE 1.1

Preparation of the coating composition

For example 1a, load beakersAgomelatine is mentioned. Addition of acrylic pressure sensitive adhesive Duro-Tak^TM(3)87-4098, and then the mixture is stirred until a clear solution is obtained (about 30 minutes).

For example 1b, a beaker was loaded with agomelatine. Addition of acrylic pressure sensitive adhesive Duro-Tak^TM(3)87-2353, and then the mixture is stirred until a viscous mixture is obtained (about 14 minutes). Next, ethyl acetate was added with stirring, and the homogeneous clear mixture was stirred for about 2.5 hours.

For example 1c, a beaker was loaded with agomelatine. The silicone pressure sensitive adhesive Q7-4302 was added and the mixture was stirred (about 10 minutes). The initial 0.6g of ethanol was added with stirring, followed by an additional 0.2g of ethanol after about 10 minutes. Next, povidone K90 was added with stirring, thereby increasing the viscosity. A slightly opaque homogeneous mixture was obtained.

Application of the coating composition

The resulting agomelatine-containing coating composition was coated on a polyester film (polyethylene terephthalate film, siliconized on one side, 100 μm thick, which can serve as the release liner of examples 1a and 1b, and 74 μm thick, which can serve as the fluoropolymer-coated release liner of example 1c) and dried at room temperature for about 10 minutes and at 60 ℃ (example 1a) and 70 ℃ (examples 1b and 1c) for about 10 minutes, respectively. The coating thicknesses in each case give 46.6g/m²(example 1a) and 49.5 (example 1b) g/m²And 50.7g/m²Areal weight of (example 1 c). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an agomelatine-containing self-adhesive layer structure.

Preparation of TTS (all examples are referred to)

The individual systems (TTS) are subsequently punched out of the self-adhesive layer structure containing agomelatine. In a particular embodiment, the TTS as described above can have a further self-adhesive layer with a large surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active agent. This is advantageous when the TTS is not sufficiently adherent to the skin on account of its individual physical properties, and/or when the agomelatine-containing matrix layer has sharp corners (square or rectangular shape) for the purpose of avoiding waste. The TTS is then punched out and sealed into pouches made of primary packaging material as is conventional in the art, i.e. under a protective atmosphere achieved by flushing with nitrogen.

Unless explicitly indicated, all TTSs described herein as examples contain no crystals as observed directly with the naked eye after preparation.

Measurement of skin permeation rate

The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to examples 1a to 1c were determined by in vitro experiments performed with 7.0ml Franz diffusion cells according to the OECD guidelines (4-month-13-day formal pass 2004). Skin from cosmetic surgery (abdomen) was used with a razor blade. For all TTS, the skin was prepared to a thickness of 800 μm with an intact epidermis using a dermatome. Punched from TTS with 1.156cm²Die-cut of area (d). The permeation amount of agomelatine in the receiving medium (phosphate buffer solution at pH 5.5 with 0.1% azide salt as antibacterial agent) of the Franz cell at a temperature of 32 ± 1 ℃ was measured and the corresponding skin permeation rate was calculated. The results are shown in table 1.2 and fig. 1 a.

TABLE 1.2

*: as in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Utilization ratio of agomelatine

The utilization of agomelatine at 8 hours was calculated based on the cumulative permeation rate at 8 and 24 hours and the initial agomelatine content. The results are shown in table 1.3 and table 1.4 and in fig. 1b and fig. 1 c.

TABLE 1.3

TABLE 1.4

In vitro experiments show that example 1c, in which the agomelatine-containing layer comprises a silicone-based PSA as the hydrophobic polymer and PVP as the crystallization inhibitor, provides excellent skin permeation rates when compared to examples 1a and 1b, which are based on acrylic polymers as the adhesive, according to certain aspects and embodiments of the present invention.

Examples 2A to 2E

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 2a to 2e are summarized in table 2.1 below. The formulations are based on weight percent, as also indicated in table 2.1.

TABLE 2.1

Preparation of the coating composition

For examples 2a to 2d, beakers were loaded with agomelatine. Separately, add solvent (ethanol for examples 2a and 2b, and ethyl acetate for examples 2c and 2d), pressure sensitive adhesive (SilAc Hybrid PSA 7-6301 for examples 2a and 2b, and Duro-Tak for examples 2c and 2d)^TM(3)87-2516) and lauryl lactate (examples 2a and 2c) or Capryol90 (examples 2b and 2 d). The mixture was then stirred. If used, polyvinylpyrrolidone (examples 2a and 2b) was added with stirring to obtain a white homogeneous mixture after about 2 hours of stirring.

For example 2e, a beaker was loaded with agomelatine. Pressure sensitive silicone adhesive Q7-4302, lauryl lactate, and ethanol were added, followed by stirring. Polyvinylpyrrolidone was added with stirring to obtain an opaque homogeneous mixture after about 2 hours of stirring.

Application of the coating composition

For examples 2a, 2b and 2e, see example 1c for the coating method. The coating thicknesses gave 47.9g/m, respectively²Example 2a) 45.7g/m²Example 2b and 55.9g/m²Areal weight of (example 2 e). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an agomelatine-containing self-adhesive layer structure.

The resulting agomelatine-containing coating compositions of examples 2c and 2d were coated on a polyethylene terephthalate film (siliconized on one side, 75 μm thick, which can act as a release liner) and dried at room temperature for about 10 minutes and at 70 ℃ for about 10 minutes. The coating thicknesses are respectively 49.1g/m²Examples 2c) and 47.8g/m²Areal weight of (example 2 d). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide a structure containing an agomelatine self-adhesive layer.

Preparation of TTS

See example 1.

Measurement of skin permeation rate

The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to examples 2a to 2e were determined as in example 1 above. Skin from cosmetic surgery (abdomen) was used with a razor blade. Punched from TTS with 1.154cm²Die-cut of area (d). The results are shown in table 2.2 and fig. 2 a.

TABLE 2.2

Utilization ratio of agomelatine

The utilization of agomelatine at 8 hours was calculated based on the cumulative permeation rate at 8 and 24 hours and the initial agomelatine content. The results are shown in tables 2.3 and 2.4 and in fig. 2b and 2 c.

TABLE 2.3

TABLE 2.4

In vitro experiments show that examples 2a and 2b, in which agomelatine-containing layers comprise a silicone acrylic hybrid polymer as the hydrophobic polymer and PVP as the crystallization inhibitor and Capryol90 or lauryl lactate as the solubilizer, provide excellent skin permeation rates when compared to examples 2c and 2d, which are based on acrylic polymers as the adhesive, according to certain aspects and embodiments of the invention. Example 2e, based on silicone-based PSA as hydrophobic polymer and PVP as crystallization inhibitor and lauryl lactate as solubilizer, provides even better skin permeation rates.

Examples 2a to 2e are all based on 4 wt% active concentration instead of 8 wt% as in examples 1a to 1c, wherein the area weight is maintained at the same level, which is why the total active content per released area is lower (about half of the total active content per released area of examples 1a to 1c) in the case of examples 2a to 2e, which may be the reason that examples 2a to 2e have a favorable release profile showing a reduced permeation rate from 8 to 24 hours compared to examples 1a to 1 c.

Examples 3A to 3D

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 3a to 3d are summarized in table 3.1 below. The formulations are based on weight percent, as also indicated in table 3.1.

TABLE 3.1

Preparation of the coating composition

For examples 3a to 3d, beakers were loaded with agomelatine. Ethanol, transcutol (example 3b) or dipropylene glycol (example 3c) or levulinic acid (example 3d) were added, and a pressure sensitive adhesive (Q7-4302) was added. The mixture was then stirred. Polyvinylpyrrolidone was added with stirring to obtain an opaque homogeneous mixture after about 3 hours of stirring.

Application of the coating composition

The resulting agomelatine-containing coating compositions of examples 3a to 3d were coated on a polyester film (74 μm thick, which can act as a fluoropolymer-coated release liner) and dried at room temperature for about 10 minutes and at 70 ℃ for about 10 minutes. The coating thicknesses are in each case 63.4g/m²Example 3a) 63.5g/m²Example 3b) 63.3g/m²Examples 3c) and 76.8g/m²Areal weight of (example 3 d). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an agomelatine-containing self-adhesive layer structure.

Microscopic observation

The agomelatine-containing layers of examples 3a to 3d were observed using a microscope (Leica DM6000M microscope with digital camera DFC450 and Leica version 4.5 application kit) shortly after manufacture and after 4 weeks of storage. The layers of all the observed examples showed droplets (approximate maximum droplet size of about 5 μm) and were therefore determined to be of the microreservoir type. Figure 3d shows a micrograph of the agomelatine-containing layer of example 3d after 4 weeks storage. Example 3d was also observed after 2 years of storage and still presented a crystal-free microreservoir with slightly larger droplets (approximate maximum droplet size of about 10 μm).

Preparation of TTS

See example 1.

Measurement of skin permeation rate

By following OECD guidelines (200)4 years, 4 months, 13 days formal pass), the permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to example 2e and 3a to 3d were determined by in vitro experiments with 7.0ml Franz diffusion cells. A razor-thick mini-pig skin (female abdomen) was used. For all TTS, the skin was prepared to a thickness of 800 μm with an intact epidermis using a dermatome. Punched from TTS with 1.154cm²Die-cut of area (d). The permeation amount of agomelatine in the receiving medium (phosphate buffer solution at pH 5.5 with 0.1% azide salt as antibacterial agent) of the Franz cell at a temperature of 32 ± 1 ℃ was measured and the corresponding skin permeation rate was calculated. The results are shown in table 3.2 and fig. 3 a.

TABLE 3.2

Utilization ratio of agomelatine

The utilization of agomelatine at 8 hours was calculated based on the cumulative permeation rate at 8 and 24 hours and the initial agomelatine content. The results are shown in tables 3.3 and 3.4 and in fig. 3b and 3 c.

TABLE 3.3

TABLE 3.4

For all test examples illustrating formulations comprising PVP as crystallization inhibitor and various substances as solubilizer, in vitro experiments showed good skin permeation rates, with a favourable release profile showing a reduction in permeation rate from 8 to 24 hours and a satisfactory utilization rate.

Examples 4A to 4E

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 4a to 4e are summarized in table 4.1 below. The formulations are based on weight percent, as also indicated in table 4.1.

TABLE 4.1

Preparation of the coating composition

For example 4a, a beaker was loaded with agomelatine. Ethyl acetate and pressure sensitive adhesive (Q7-4302) were added. The mixture was then stirred to obtain a clear mixture after about 2 hours.

For examples 4b to 4e, the beakers were loaded with agomelatine. Solvents (ethyl acetate for example 4b and ethanol for examples 4c to 4e), dipropylene glycol (examples 4b and 4d) or levulinic acid (example 4e) and pressure-sensitive adhesives (Q7-4302) were added. The mixture was then stirred. If used, polyvinylpyrrolidone (examples 4c to 4e) was added with stirring to obtain an opaque homogeneous mixture after about 1 to 2 hours of stirring.

Application of the coating composition

The resulting agomelatine-containing coating compositions of examples 4a to 4e were coated on a polyester film (74 μm thick, which can act as a fluoropolymer-coated release liner) and dried at room temperature for about 10 minutes, and at 60 ℃ for about 10 minutes (examples 4a and 4b), and at 70 ℃ for about 10 minutes (examples 4c to 4e), respectively. Coating and drying were repeated as necessary to achieve the desired coating thickness. The coating thicknesses are each 41.9g/m²Example 4a) 41.9g/m²Example 4b) 45.3g/m²Example 4c) 52.2g/m²Example 4d) and 46.7g/m²Areal weight of (example 4 e). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an agomelatine-containing self-adhesive layer structure.

Microscopic observation

Shortly after manufacture, the agomelatine-containing layers of examples 4b and 4c were observed using a microscope (Leica DM6000M microscope with digital camera DFC450 and Leica version 4.5 application kit). These layers showed droplets (approximate maximum droplet sizes of about 10 and 15 μm) and were therefore identified as being microreservoir. Figure 4d shows a micrograph of the agomelatine-containing layer of example 4c 1 day after manufacture.

Preparation of TTS

See example 1.

Measurement of skin permeation rate

The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to examples 4a to 4e were determined as in example 3 above. The results are shown in table 4.2 and fig. 4 a.

TABLE 4.2

Utilization ratio of agomelatine

The utilization of agomelatine at 8 hours was calculated based on the cumulative permeation rate at 8 and 24 hours and the initial agomelatine content. The results are shown in tables 4.3 and 4.4 and in fig. 4b and 4 c.

TABLE 4.3

TABLE 4.4

These examples show that agomelatine utilisation and release profile as determined by in vitro experiments for examples 4c, 4d and 4e including PVP as crystallisation inhibitor in the agomelatine-containing layer is much better in terms of rapid onset of penetration and absolute penetration rate and reduction of penetration from 8 hours to 24 hours when compared to examples 4a and 4 b.

Examples 5A to 5D

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 5a to 5d are summarized in table 5.1 below. The formulations are based on weight percent, as also indicated in table 5.1.

TABLE 5.1

Preparation of the coating composition

For examples 5a and 5c, beakers were loaded with agomelatine. Dipropylene glycol, pressure sensitive adhesive (SilAc PSA 7-6301), and if used, polyvinylpyrrolidone (example 5c) were added. The mixture was then stirred. Ethanol was added with stirring. After about 1 to 2 hours a white homogeneous mixture was obtained (examples 5a and 5 c).

For example 5b, a beaker was loaded with agomelatine. Polyvinylpyrrolidone, dipropylene glycol and a sticker (Oppanol B10/B10085/15) were added, followed by mixing to obtain an opaque homogeneous mixture after about 3 hours.

For example 5d, a beaker was loaded with agomelatine. Pressure sensitive adhesive (Q7-4302) was added. The mixture was then stirred. Polyvinylpyrrolidone and ethanol were added with stirring to obtain an opaque homogeneous mixture after about 1 hour.

Application of the coating composition

The obtained agomelatine-containing coating compositions of examples 5a to 5d were coated on a polyester film (74 μm thickness, which can serve as the fluoropolymer of examples 5a, 5c and 5d)Coated release liner, and polyethylene terephthalate film siliconized on one side, 75 μm thick, which can serve as the release liner of example 5b) and dried at room temperature for about 10 minutes, and at 70 ℃ for about 10 minutes (examples 5a, 5c and 5d), and at 90 ℃ for about 10 minutes (example 5b), respectively. The coating thicknesses are in each case 37.4g/m²Example 5a) 64.6g/m²Example 5b) 52.8g/m²Example 5c) and 60.6g/m²Areal weight of (example 5 d). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an agomelatine-containing self-adhesive layer structure.

Microscopic observation

The agomelatine-containing layers of examples 5a to 5d were observed shortly after manufacture (3-4 days, examples 5a and 5d) and after about 32 months (examples 5b and 5c) using a microscope (Leica DM6000M microscope with digital camera DFC450 and Leica version 4.5 application kit). The layers of all examples show droplets and are therefore determined to be of the microreservoir type. Example 5d (based on silicone-based PSA as hydrophobic polymer) shows a maximum droplet size of about 15 μm, whereas the droplet size of example 5b (based on polyisobutylene as hydrophobic polymer) is relatively large (maximum droplet size of about 60 μm). The droplet size in the case of examples 5a and 5c (silicone acrylic based hybrid PSA as hydrophobic polymer) was so small that under microscope the droplets were difficult to discern by the naked eye. Fig. 5c and 5d show micrographs of agomelatine-containing layers of examples 5b and 5d, respectively.

Preparation of TTS

See example 1.

Measurement of skin permeation rate

The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to examples 5a to 5d were determined as in example 3 above. The results are shown in table 5.2 and fig. 5 a.

TABLE 5.2

Utilization ratio of agomelatine

The utilization rate of agomelatine at 8 hours was calculated based on the cumulative permeation amount at 8 hours and the initial agomelatine content. The results are shown in table 5.3 and fig. 5 b.

TABLE 5.3

These examples show that the agomelatine utilisation and release profile as determined by in vitro experiments is much better for example 5d, which is based on a silicone-based PSA as hydrophobic polymer, in terms of fast onset of permeation and absolute permeation rate when compared to examples 5a to 5c, which are based on a silicone acrylic hybrid polymer or polyisobutylene as hydrophobic polymer.

Examples 6A to 6D

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 6a to 6d are summarized in table 6.1 below. The formulations are based on weight percent, as also indicated in table 6.1.

TABLE 6.1

Preparation of the coating composition

For example 6a, a beaker was loaded with agomelatine and dissolved in ethanol. Pressure sensitive adhesive (Q7-4202), polyvinylpyrrolidone and dipropylene glycol were added with stirring. An opaque mixture was obtained after about 3 hours.

For example 6b, the beaker was loaded with agomelatine. Addition of isopropanol and pressure-sensitive adhesive (Q7-4402 and Duro-Tak)^TM(3)87-4287). The mixture was then stirred to obtain an opaque mixture after about 2 hours.

For examples 6c and 6d, beakers were loaded with agomelatine. Ethanol and a pressure sensitive adhesive (SIS-Arkon) were added. The mixture was then stirred. Heptane and polyvinylpyrrolidone (example 6c) and dipropylene glycol (example 6d) were added separately with stirring to obtain an opaque homogeneous mixture after about 1 hour (examples 6c and 6 d).

Furthermore, a new batch of example 3c was prepared according to the formulation of the agomelatine-containing coating composition as outlined in table 3.1 above, wherein the difference in the amounts of the formulation ingredients used was negligible.

Application of the coating composition

The resulting agomelatine-containing coating compositions of examples 6a to 6d were coated on a polyester film (74 μm thick, which can serve as the fluoropolymer-coated release liner of examples 6a and 6b, and a polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as the release liner of examples 6c and 6d) and dried at room temperature for about 10 minutes and at 70 ℃ for about 10 minutes. The coating thicknesses are respectively 61.2/m²Example 6a) 57.5g/m²Example 6b) 58.6g/m²Example 6c) and 65.6g/m²Areal weight of (example 6 d). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an agomelatine-containing self-adhesive layer structure.

For the coating of a new batch of example 3c, see the procedure outlined above for coating the initial batch of example 3 c. The coating thickness gives 64.5g/m²Thereby obtaining an areal weight of 257.5. mu.g/cm²Agomelatine content of (a).

Microscopic observation

Shortly after manufacture (days up to 2 weeks), the agomelatine-containing layers of examples 6a, 6c and 6d were observed using a microscope (Leica DM6000M microscope with digital camera DFC450 and Leica version 4.5 application kit). The layers of all examples show droplets and are therefore determined to be of the microreservoir type. Examples 6c and 6d (based on styrene isoprene styrene adhesive as hydrophobic polymer) show relatively large droplets with maximum droplet sizes of about 30 and 60 μm, respectively, whereas example 6a (based on silicone based PSA as hydrophobic polymer) has droplet sizes that are small compared to them (maximum droplet size of about 15 μm). Fig. 6c and 6d show micrographs of agomelatine-containing layers of examples 6a and 6c, respectively.

Preparation of TTS

See example 1.

Measurement of skin permeation rate

The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to examples 6a to 6d and of the new batch of example 3c were determined as in example 3 above. Punched from TTS with 1.151cm²Die-cut of area (d). The results are shown in table 6.2 and fig. 6 a.

TABLE 6.2

Utilization ratio of agomelatine

The utilization of agomelatine at 8 hours was calculated based on the cumulative permeation rate at 8 and 12 hours and the initial agomelatine content. The results are shown in tables 6.3 and 6.4 and figure 6 b.

TABLE 6.3

TABLE 6.4

In the case of example 6b, the effect of isopropanol as a penetration enhancer in combination with a mixture of acrylate polymer and silicone-based PSA was explored. Surprisingly, examples 6a and 3c, which are based on silicone-based PSAs as hydrophobic polymers and include PVP as a crystallization inhibitor and dipropylene glycol as a solubilizer, according to certain embodiments of the present invention, show the most excellent permeation characteristics. Furthermore, examples 6c and 6d, which are based on styrene isoprene styrene adhesive as the hydrophobic polymer, show much better penetration characteristics and utilization, although not to the same extent as examples 6a and 3 c.

Examples 7A to 7D

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 7a to 7d and 3 d' are summarized in table 7.1 below. The formulations are based on weight percent, as also indicated in table 7.1.

TABLE 7.1

Preparation of the coating composition

For examples 7a, 7b, the beakers were loaded with agomelatine. Pressure sensitive adhesive (Q7-4302) and Brij L4 (example 7a) and levulinic acid (example 7b) were added separately. The mixture was then stirred. Polyvinylpyrrolidone and ethanol were added with stirring. A clear mixture was obtained after about 1 to 2 hours of stirring.

For example 7c, a beaker was loaded with agomelatine. Ethanol, Capryol90, and pressure sensitive adhesive (Q7-4302) were added. The mixture was then stirred. Polyvinylpyrrolidone was added with stirring. An opaque mixture was obtained after about 1 hour of stirring.

For example 7d, a beaker was loaded with agomelatine. Pressure sensitive adhesive (Q7-4302) and ethanol were added. The mixture was then stirred. Polyvinylpyrrolidone was added with stirring. An opaque homogeneous mixture was obtained after about 1 hour of stirring.

Furthermore, a new batch of example 3d was prepared according to the formulation of the agomelatine-containing coating composition as outlined in table 3.1 above, wherein the difference in the amounts of the formulation ingredients used was negligible.

Application of the coating composition

The resulting agomelatine-containing coating compositions of examples 7a to 7d were coated on a polyester film (74 μm thick, which can serve as the fluoropolymer-coated release liner of examples 7a to 7d) and dried at room temperature for about 10 minutes, and at 70 ℃ for about 10 minutes (examples 7a to 7 d). The coating thicknesses are respectively 51.4/m²Example 7a) 51.6g/m²Example 7b) 42.7g/m²Examples 7c) and 53.4g/m²Areal weight of (example 7 d). The dried film was laminated with a polyethylene terephthalate backing layer (19 μm thickness for examples 7a and 7b and 23 μm for examples 7c and 7d) to provide an agomelatine-containing self-adhesive layer structure.

For the coating of the new batch of example 3d, see the procedure outlined above for coating the initial batch of example 3 d. The coating thickness gave 65.3g/m²Thereby obtaining 260.5. mu.g/cm²Agomelatine content of (a).

Microscopic observation

The agomelatine-containing layer of example 7d and the agomelatine-containing layer prepared in a similar manner to examples 7a and 7b (new batch) were observed using a microscope (Leica DM6000M microscope, with digital camera DFC450 and Leica version 4.5 application kit) after 2 to 4 weeks of storage (new batch of examples 7a and 7d) and after 21 months of storage (new batch of example 7 b). These layers show droplets and are therefore identified as microreservoir. The droplet size is relatively uniform and several microns in size.

Preparation of TTS

See example 1.

Measurement of skin permeation rate

Root determination as in example 3 aboveThe TTS prepared according to examples 7a to 7d and the permeation amounts and corresponding skin permeation rates of the new batch of example 3 d. Punched from TTS with 1.188cm²Die-cut of area (d). The results are shown in table 7.2 and fig. 7 a.

TABLE 7.2

Utilization ratio of agomelatine

The utilization of agomelatine at 8 hours was calculated based on the cumulative permeation rate at 8 and 24 hours and the initial agomelatine content. The results are shown in tables 7.3 and 7.4 and in fig. 7b and 7 c.

TABLE 7.3

TABLE 7.4

The in vitro experiments of all examples show good skin permeation rate and release profile, wherein, however, the use of a new batch of 4 wt% agomelatine in combination with PVP as crystallization inhibitor and levulinic acid as solubilizer, example 3d, is much better when compared to example 7b, which uses the same formulation but only 2 wt% agomelatine. The skin permeation rate and release profile of examples 7a, 7c and 7d are similar and intermediate between that of example 7b and that of the new batch of example 3d, even though example 7d, which does not include a solubilizing agent, uses 4 wt% agomelatine, whereas examples 7a and 7c contain only 2 wt% agomelatine, but includes Brij or Capryol as solubilizing agent.

In vivo studies using a gottingen miniature pig (Goettinggen minipig)

To assess the local tolerance of agomelatine, in vivo experiments using gottingen miniature pigs (female, about 6 to 7 months, body weight 13.8-14.3kg at the start of the study) were performed. TTS prepared from the above examples 3d (new batch), 7a, 7b and 7c, and punched with 10cm from two other agomelatine TTS and from six corresponding placebo TTS²Die-cut of area (d). Six drug-containing TTS and six placebo TTS were used one each as a cut (10 cm each) per piglet²) In total, twelve TTSs. TTS from 40cm²(6.3 x 6.3cm) the cover patch was fixed in place and the application site was additionally covered with a gauze dressing to hold the patch in place and prevent the animal from disturbing the patch. Four piglets were used. The total wear time of all 12 patches (6 actives and 6 placebo) per mini-pig was 12 hours for animals No. 1 and 2 and 24 hours for animals No. 3 and 4.

During the study, the piglets were kept at 21 ± 3 ℃, lighted from 6 am to 6 pm, and each animal was fed twice daily with approximately 175g of SDS mini pig diet (smp (e) SQC) from Special diet Services, and water was taken ad libitum.

After removal of the TTS according to the total wearing time as outlined above, the separation was quantified in percentage (0% to 100%) and the overall adhesion was determined qualitatively (good adhesion, easy separation, complete separation).

Furthermore, immediately after the TTS was removed and 12 hours after removal, the skin condition was determined macroscopically and a draez (Draize) score was obtained based on the following scoring procedure according to the guidelines for chemical testing of OECD number 404, which is formally passed on day 28, 7/2015: "Acute skin Irritation/Corrosion (Acute skin Irition/Corrosion)".

Skin (sites 1-12) from the site of administration (intact site covered by patch) was collected and one skin sample from the untreated area was taken from each animal as a reference for histopathological examination. Samples from all animals were trimmed and representative specimens were taken for histological processing. The specimens were embedded in paraffin and cut at a nominal thickness of 5 μm, stained with hematoxylin and eosin, and examined under an optical microscope. Histopathological examination of the epidermis and dermis did not reveal agomelatine or TTS related findings.

For all formulations, the TTS tack (in percent tack area) was between 34% and 76% after 12/24 hours (see table 7.5). It is believed that the reason for the lower patch adhesion area of 34% in the TTS according to example 3d is the location of application of the TTS located next to the small pig's limb. This is why the adhesion seems to be lower compared to other formulations. The adhesion of examples 7a to 7c ranged between 60 and 76%.

None of the formulations showed skin irritation 12 hours after TTS removal. The skin at the application site of the TTS according to examples 7a and 7b showed an extremely slight skin irritation with a derez score of 1 only immediately after removal of the TTS and cleaning of the application site (table 7.5). Subsequent histopathological evaluation of the drug-containing administration area (12 hours after TTS removal) showed no API/TTS-related study results. The recorded findings were considered to be within the background variation seen in the skin of the gotine miniature pigs of this age and, therefore, not treatment-related. These results demonstrate that the risk of skin irritation potential of the TTS of the invention is lower.

TABLE 7.5

*: values are given for mini-pig # 1/2/3/4, respectively.

**: scoring procedure for assessing skin irritation potential according to the derez method:

0 ═ no erythema, no edema, 1 ═ very mild erythema (visible), very mild edema (visible), 2 ═ well-defined erythema, mild edema, 3 ═ moderate to severe erythema, moderate edema, 4 ═ severe erythema, severe edema.

Examples 8A to 8D

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 8a to 8d are summarized in table 8.1 below. The formulations are based on weight percent, as also indicated in table 8.1.

TABLE 8.1

Preparation of the coating composition

For example 8a, a beaker was loaded with agomelatine. Ethanol, levulinic acid and pressure sensitive adhesive (Q7-4302) were added. The mixture was then stirred. Polyvinylpyrrolidone was added with stirring. A clear mixture was obtained after about 4 hours of stirring (example 8 a).

For example 8b, a stainless steel container was loaded with agomelatine. Ethanol, levulinic acid and pressure sensitive adhesive (Q7-4302) were added. The mixture was then stirred. Polyvinylpyrrolidone was added with stirring. A clear mixture was obtained after about 3 hours of stirring (example 8 b).

For examples 8c and 8d, beakers were loaded with agomelatine. Pressure sensitive adhesive (Q7-4302) and ethanol were added. The mixture was then stirred. Polyvinylpyrrolidone was added with stirring. A clear mixture was obtained after stirring for about 2 hours (example 8c) and 5 hours (example 8d), respectively.

Application of the coating composition

The resulting agomelatine-containing coating compositions of examples 8a to 8d were coated on a polyester film (74 μm thick, which can act as a fluoropolymer-coated release liner) and dried at room temperature for about 10 minutes and at 70 ℃ for about 10 minutes. The coating thicknesses are each 50.1/m²Example 8a) 50.0g/m²Example 8b) 49.2g/m²Example 8c) and 52.0g/m²Areal weight of (example 8 d). The dried film was combined with a polyethylene terephthalate backing layer (for examples 8a to 8d)Is 19 μm thick) are laminated together to provide an agomelatine-containing self-adhesive layer structure.

Microscopic observation

The agomelatine-containing layers of examples 8b and 8d were observed after 4 to 5 months of storage using a microscope (Leica DM6000M microscope with digital camera DFC450 and Leica version 4.5 application kit). These layers show droplets and are therefore identified as microreservoir. The droplet size is relatively uniform and in size is a few microns (maximum droplet size of about 10 μm). Fig. 8c and 8d show micrographs of agomelatine-containing layers of examples 8b and 8d, respectively.

Preparation of TTS

See example 1.

Measurement of skin permeation rate

The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to examples 8a to 8d were determined as in example 1 above. The skin of the razor blades from cosmetic surgery (female abdomen, birth date 1976) was used. For all TTS, the skin was prepared to a thickness of 500 μm with an intact epidermis using a dermatome. Punched from TTS with 1.157cm²Die-cut of area (d). The results are shown in table 8.2 and fig. 8 a.

TABLE 8.2

Utilization ratio of agomelatine

The utilization rate of agomelatine at 8 hours was calculated based on the cumulative permeation amount at 8 hours and the initial agomelatine content. The results are shown in table 8.3 and fig. 8 b.

TABLE 8.3

In vitro experiments showed that both formulations had good skin penetration rate and availability, but the addition of levulinic acid in example 8a/8b appeared to be more advantageous when compared to the formulation of example 8c/8d, which contained higher amounts of PVP but no solubilizer.

Measurement of storage stability

Examples 8b and 8d were tested for long term storage stability under different test conditions, i.e., storage at 25 ℃ and 60% Relative Humidity (RH), at 30 ℃ and 75% RH, and at 40 ℃ and 75% RH. Samples were taken of the TTS after 3, 6, 9 and 12 months of storage at 25 ℃ and 60% RH, after 9 and 12 months of storage at 30 ℃ and 75% RH and after 3 and 6 months of storage at 40 ℃ and 75% RH, and the amount of agomelatine and of the various possible degradation substances was determined by a specific quantitative HPLC method based on the agomelatine content calculated from the (actual) areal weight of the tested TTS. The adhesion of the adhesive layer on the steel plate and the peeling force of the adhesive layer from the release liner were measured at an angle of 90 ° and at a test speed of 300mm/min for the adhesion and 150mm/min for the peeling force using a 45.0mm × 45.0mm sample. It was further tested whether the removability of the adhesive layer from the release liner was ensured and the compliance was recorded. Furthermore, cold flow that may occur is visually inspected and compliance with a still acceptable degree of cold flow is recorded. The results are shown in tables 8.4 to 8.9 and in fig. 8e to 8 h.

TABLE 8.4

N.d. -, not detected

TABLE 8.5

N.d. -, not detected

TABLE 8.6

N.d. not detected, N/a is not data

TABLE 8.7

N.d. not detected, N/a is not data

TABLE 8.8

N.d. not detected, N/a is not data

TABLE 8.9

N.d. not detected, N/a is not data

The stability data show that the initial and storage stability of examples 8b and 8d is excellent both in terms of the amount of agomelatine (in particular with respect to the amount of agomelatine remaining after storage) and in terms of the sum of possible degradation substances.

The adhesion was also maintained at a good level over time with only a slight decrease.

Although the peel force increased slightly with time, the increase was well within an acceptable range, and removability from the release liner was always ensured. Delamination of the adhesive or cohesive layers of the release liner is not expected.

In general, long shelf lives of, for example, 12 or 24 months or more are envisaged.

Examples 9A to 9E

Coating composition

The formulations of the agomelatine-containing coating compositions of examples 9a to 9g are summarized in table 9.1 below. The formulations are based on weight percent, as also indicated in table 9.1.

TABLE 9.1

Preparation of the coating composition

For example 9a, a beaker was loaded with agomelatine. Ethanol and polyvinylpyrrolidone were added and the mixture was allowed to stand for 3 hours. The silicone acrylic hybrid PSA adhesive was added and the mixture was stirred at 1000 rpm. A white homogeneous mixture was obtained.

For example 9b, a beaker was loaded with agomelatine. Ethanol and pressure sensitive adhesive (Q7-4202) were added and the mixture was stirred. The polyvinylpyrrolidone was added with stirring and the mixture was stirred again. A cloudy homogeneous solution was obtained.

For example 9c, a beaker was loaded with agomelatine. Polyisobutylene adhesive and ethyl acetate were added and the mixture was allowed to stand for 1 hour. Polyvinylpyrrolidone was added, the mixture was stirred at 250rpm, and ethanol was added after 0.5 hours. A clear solution with visible small bubbles was obtained.

For example 9d, a beaker was loaded with agomelatine and dissolved in 1.5g of ethanol. Polyvinylpyrrolidone was added and the mixture was allowed to stand for about 1 hour. Styrene isoprene styrene adhesive was added and the mixture was stirred at 200 rpm. Finally, the remaining part of ethanol and n-heptane was added and the mixture was stirred at 200 rpm. A slightly turbid solution with no visible crystals was obtained.

For example 9e, a beaker was loaded with agomelatine. Dipropylene glycol was added and the mixture was stirred. Ethyl acetate and pressure sensitive adhesive (Q7-4301) were added. The mixture was then stirred. A clear solution was obtained after about 2.5 hours of stirring.

Application of the coating composition

The resulting agomelatine-containing coating compositions of examples 9a to 9d were coated on a polyester film (74 μm thick, which can act as a fluoropolymer-coated release liner) and dried at room temperature for about 10 minutes and at 70 ℃ for about 10 minutes. The coating thicknesses are respectively given 45.5/m²Example 9a) 47.0g/m²Example 9b) 57.6g/m²Example 9c) and 50.4g/m²Areal weight of (example 9 d). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness for examples 9a, 9b, 9c and 9d) to provide an agomelatine-containing self-adhesive layer structure.

Microscopic observation

The agomelatine-containing layers of examples 9a to 9e were observed using a microscope (Leica DM6000M microscope with digital camera DFC450 and Leica version 4.5 application kit) immediately after manufacture (1 to 3 days) (examples 9a and 9b) or after storage for about 2 weeks (example 9c), 3 weeks (example 9d) or 2.5 months (example 9 e). All of these layers contain crystals. Figures 9a to 9e show micrographs of agomelatine-containing layers of examples 9a to 9e, respectively.

Preparation of TTS

See example 1.

The invention relates in particular to the following further items:

1. transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i) agomelatine;

ii) a hydrophobic polymer; and

wherein

2. Transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i) agomelatine; and

ii) a hydrophobic polymer;

wherein

the agomelatine-containing layer belongs to a microreservoir type.

3. The transdermal therapeutic system in accordance with item 2,

wherein the agomelatine-containing layer further comprises a crystallization inhibitor, or comprises at least 1 wt% of a crystallization inhibitor.

4. The transdermal therapeutic system in accordance with item 3,

wherein the crystallization inhibitor is selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinylacetate copolymer.

5. The transdermal therapeutic system according to any one of

items

1, 3 and 4,

wherein the agomelatine-containing layer comprises at least 1.5 wt%, at least 2.5 wt%, at least 4 wt%, or at least 5 wt% of the crystallization inhibitor.

6. The transdermal therapeutic system according to any one of

items

1 and 3 to 5,

wherein the crystallization inhibitor is polyvinylpyrrolidone, or

Wherein the crystallization inhibitor is selected from soluble polyvinylpyrrolidone.

7. The transdermal therapeutic system according to any one of

items

1 and 3 to 6,

wherein the crystallization inhibitor is selected from polyvinylpyrrolidone having a K value within a range selected from the group of ranges consisting of

9 to 15, and preferably 10.2 to 13.8,

15 to 20, and preferably 15.3 to 18.4,

20 to 27, and preferably 22.5 to 27.0,

27 to 35, and preferably 27.0 to 32.4, and

75 to 110, and preferably 81.0 to 97.2.

8. The transdermal therapeutic system according to any one of items 1 to 7,

wherein the agomelatine-containing layer comprises a solubilizing agent selected from the group consisting of: dipropylene glycol, lauryl lactate, mixtures of propylene glycol mono-and diesters of fatty acids, levulinic acid, polyethylene glycol ether, and diethylene glycol monoethyl ether.

9. The transdermal therapeutic system in accordance with item 8,

wherein the agomelatine-containing layer comprises at least 1.5 wt%, at least 2.5 wt%, at least 4 wt%, or at least 5 wt% of the solubilizing agent, or

Wherein the agomelatine-containing layer does not comprise a solubilizing agent selected from the group consisting of: dipropylene glycol, lauryl lactate, mixtures of propylene glycol mono-and diesters of fatty acids, levulinic acid, polyethylene glycol ether, and diethylene glycol monoethyl ether.

10. The transdermal therapeutic system according to any one of

items

1 and 3 to 9,

wherein the agomelatine-containing layer comprises a crystallization inhibitor and the total amount of crystallization inhibitor and solubilizer present in the agomelatine-containing layer is at least 2.5 wt.%, at least 3.5 wt.%, at least 4 wt.% or at least 5 wt.%, or

Wherein the ratio of the total amount of crystallization inhibitor and solubilizer present in the agomelatine-containing layer to the amount of agomelatine present in the agomelatine-containing layer is at least 1:2, at least 1:1, or at least 2: 1.

11. The transdermal therapeutic system according to any one of items 1 to 10,

wherein the agomelatine-containing layer comprises at least 0.5 wt% agomelatine, at least 1 wt% agomelatine or at least 1.5 wt% agomelatine, or

Wherein the agomelatine-containing layer comprises less than or equal to 8 wt% agomelatine, less than or equal to 6 wt% agomelatine, or less than or equal to 5 wt% agomelatine, or

Wherein the agomelatine-containing layer comprises 0.5 to less than or equal to 8 wt% agomelatine, 1 to less than or equal to 6 wt% agomelatine, or 1.5 to less than or equal to 5 wt% agomelatine.

12. The transdermal therapeutic system according to any one of items 1 to 11,

wherein the hydrophobic polymer is selected from pressure sensitive adhesive polymers.

13. The transdermal therapeutic system according to any one of items 1 to 12,

wherein the hydrophobic polymer is a silicone-based pressure sensitive adhesive.

14. The transdermal therapeutic system in accordance with item 13,

wherein the polysiloxane-based pressure-sensitive adhesive is a soluble silicate resin condensed with silanol-terminated polydimethylsiloxane.

15. The transdermal therapeutic system in accordance with item 14,

wherein the polysiloxane-based pressure sensitive adhesive is a soluble silicate resin polycondensed with a silanol terminated polydimethylsiloxane having a resin to polymer ratio of 65:35, 60:40, or 55: 45.

16. The transdermal therapeutic system according to item 15,

wherein those silanol groups of the polydimethylsiloxane that are not attached to the soluble silicate resin are free silanol groups, or are trimethylsilylated.

17. The transdermal therapeutic system according to any one of items 13 to 16,

wherein the polysiloxane-based pressure-sensitive adhesive is characterized by a solution viscosity of greater than about 150mPa · s, or from about 200mPa · s to about 700mPa · s, at 25 ℃ and 60% solids in n-heptane, preferably as measured using a Brookfield RVT viscometer equipped with a rotor number 5 at 50rpm, or by a complex viscosity of less than about 1x10 at 0.01rad/s at 30 ℃⁹Poise, or about 1x10⁵To about 9x10⁸Poise, or

Wherein the polysiloxane-based pressure-sensitive adhesive is characterized by a solution viscosity of greater than about 350mPa · s, or from about 400mPa · s to about 1500mPa · s, at 25 ℃ and 60% solids in ethyl acetate, preferably as measured using a Brookfield RVT viscometer equipped with a rotor number 5 at 50rpm, or by a complex viscosity of about 1x10 at 0.01rad/s at 30 ℃⁵To about 1x10⁷Poise or about 5x10⁶Poise.

18. The transdermal therapeutic system according to any one of items 1 to 12,

wherein the hydrophobic polymer is polyisobutylene.

19. The transdermal therapeutic system according to item 18,

wherein the hydrophobic polymer is a polymer having a viscosity average molecular weight M of 1,110,000_v1,550,000, a weight average molecular weight M_wAnd an average molecular weight distribution M of 2.9_w/M_nOr a high molecular weight polyisobutylene having a viscosity average molecular weight M of 40,000_vWeight average molecular weight M of 53,000_wAnd an average molecular weight distribution M of 3.2_w/M_nOf low molecular weight polyisobutene, orIs a mixture thereof, or

Wherein the hydrophobic polymer is a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene, wherein the ratio of low molecular weight polyisobutylene to high molecular weight polyisobutylene is in the range of 100:1 to 1:100, or 60:40 to 20:80, or 50:50 to 30: 70.

20. The transdermal therapeutic system according to any one of items 1 to 12,

wherein the hydrophobic polymer is a styrene-isoprene-styrene block copolymer.

21. The transdermal therapeutic system according to any one of items 1 to 12,

wherein the hydrophobic polymer is a silicone acrylic hybrid polymer.

22. The transdermal therapeutic system according to any one of items 1 to 21,

wherein the agomelatine-containing layer comprises substantially no isopropanol.

23. The transdermal therapeutic system according to item 22,

wherein the agomelatine-containing layer comprises less than or equal to 5 wt%, less than or equal to 3 wt%, or less than or equal to 1 wt% isopropanol.

24. The transdermal therapeutic system according to any one of items 1 to 23,

wherein the agomelatine-containing layer is substantially free of volatile solvents,

wherein the volatile solvent is selected from the group consisting of: c1 to C3 straight and branched chain alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof.

25. The transdermal therapeutic system according to item 24,

wherein the agomelatine-containing layer comprises less than or equal to 5 wt%, less than or equal to 3 wt%, or less than or equal to 1 wt% of a volatile solvent.

26. The transdermal therapeutic system according to any one of items 1 to 25,

wherein the agomelatine-containing layer does not comprise an acrylic polymer in an amount greater than 70 wt%, greater than 50 wt%, or greater than 30 wt% relative to the agomelatine-containing layer.

27. The transdermal therapeutic system according to any one of items 1 to 26,

wherein the agomelatine-containing layer is of microreservoir type or of matrix type,

wherein the agomelatine is completely dissolved, or in dispersed form.

28. The transdermal therapeutic system according to any one of items 1 to 26,

wherein the agomelatine-containing layer is a dry biphasic layer having

a) An external phase having a pressure-sensitive adhesive composition comprising the hydrophobic polymer, and

b) an internal phase having a composition comprising the agomelatine,

wherein the inner phase forms dispersed deposits in the outer phase.

29. The transdermal therapeutic system according to item 28,

wherein the composition of the inner phase comprises a crystallization inhibitor, and/or

Wherein the pressure sensitive adhesive composition of the outer phase is substantially free of crystallization inhibitors.

30. The transdermal therapeutic system according to item 29,

wherein the pressure sensitive adhesive composition of the outer phase comprises less than or equal to 5 wt%, less than or equal to 3 wt%, or less than or equal to 1 wt% crystallization inhibitor.

31. The transdermal therapeutic system according to item 28,

wherein the composition of the internal phase is substantially free of hydrophobic polymers.

32. The transdermal therapeutic system according to item 31,

wherein the composition of the inner phase comprises less than or equal to 5 wt%, less than or equal to 3 wt%, or less than or equal to 1 wt% hydrophobic polymer.

33. The transdermal therapeutic system of any one of items 28 to 32,

wherein the dispersed deposits have an average particle size of 0.1 to 100 μm, or 0.5 to 50 μm.

34. The transdermal therapeutic system according to any one of items 1 to 33,

wherein the agomelatine-containing layer does not contain agomelatine crystals.

35. The transdermal therapeutic system according to any one of items 1 to 34,

wherein the agomelatine-containing layer has at least 25g/m²At least 35g/m²Or at least 40g/m²Or an areal weight of less than or equal to 150g/m²Less than or equal to 120g/m²Or less than or equal to 90g/m²Or an areal weight of from 25 to 150g/m²35 to 120g/m²Or 40 to 90g/m²Area weight of (c).

36. The transdermal therapeutic system according to any one of items 1 to 35,

wherein the transdermal therapeutic system has at least 1cm²At least 5cm²Or at least 10cm²Or has a release area of less than or equal to 100cm²Less than or equal to 60cm²Or less than or equal to 50cm²Or has a release area of 1 to 100cm ²5 to 60cm²Or 10 to 50cm²The area of release of (a).

37. The transdermal therapeutic system according to any one of items 1 to 36,

wherein the agomelatine-containing layer contains at least 0.04mg/cm²At least 0.06mg/cm²At least 0.08mg/cm²Or at least 0.1mg/cm²Agomelatine, or wherein the agomelatine-containing layer comprises less than or equal to 0.4mg/cm²Less than or equal to 0.3mg/cm²Less than or equal to 0.25mg/cm²Or less than or equal to 0.2mg/cm²Agomelatine.

38. The transdermal therapeutic system according to any one of the items 1 to 37,

wherein the agomelatine-containing layer is obtainable by drying a coated coating composition comprising the agomelatine, the hydrophobic polymer, optionally the crystallization inhibitor and ethanol.

39. The transdermal therapeutic system according to any one of items 1 to 38,

wherein the agomelatine-containing layer is obtainable by drying a coated coating composition comprising less than 1 wt%, less than 0.5 wt% or less than 0.1 wt% water.

40. The transdermal therapeutic system according to any one of items 1 to 39,

wherein the agomelatine is included in the agomelatine-containing layer in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, mixed form of any of the foregoing forms or a mixture thereof.

41. The transdermal therapeutic system according to any one of items 1 to 40,

wherein the agomelatine-containing layer is obtainable by incorporating the agomelatine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, mixed form of any of the foregoing forms or a mixture thereof.

42. The transdermal therapeutic system according to any one of clauses 1 to 41,

wherein the agomelatine in the agomelatine-containing layer is dissolved or is present in dispersed form.

43. The transdermal therapeutic system according to any one of items 1 to 42,

wherein at least 90 mol%, at least 95 mol%, at least 98 mol% or at least 99 mol% of the agomelatine-containing layer is present in dissolved form.

44. The transdermal therapeutic system according to any one of items 1 to 43,

wherein the agomelatine has a purity of at least 95%, preferably at least 98% and more preferably at least 99%, as determined by quantitative HPLC.

45. The transdermal therapeutic system according to any one of items 1 to 44,

wherein the agomelatine-containing layer is a pressure-sensitive adhesive layer.

46. The transdermal therapeutic system according to any one of items 1 to 45,

wherein the amount of the hydrophobic polymer is at least 75 wt%, at least 80 wt%, or at least 75 wt%, or the amount of the hydrophobic polymer is less than or equal to 98 wt%, less than or equal to 94 wt%, or less than or equal to 90 wt%, or the amount of the hydrophobic polymer is in the range of 75 to 98 wt%, 80 to 94 wt%, or 85 to 90 wt% relative to the agomelatine-containing layer.

47. The transdermal therapeutic system according to any one of items 1 to 46,

wherein the amount of agomelatine contained in the transdermal therapeutic system is at least 0.5mg, at least 1mg, or at least 2mg, or the amount of agomelatine contained in the transdermal therapeutic system is less than or equal to 15mg, less than or equal to 10mg, or less than or equal to 8mg, or the amount of agomelatine contained in the transdermal therapeutic system is in the range of 0.5 to 15mg, or 1 to 10mg, or 2 to 8 mg.

48. The transdermal therapeutic system according to any one of items 1 to 47,

wherein the agomelatine-containing layer comprises further excipients or additives selected from the group consisting of: cross-linking agents, other solubilizers, fillers, tackifiers, plasticizers, stabilizers, emollients, skin care substances, permeation enhancers, pH modifiers, and preservatives.

49. The transdermal therapeutic system according to item 48,

wherein the tackifier is selected from the group consisting of triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes, and polybutenes.

50. The transdermal therapeutic system according to item 48,

wherein the stabilizer is selected from sodium metabisulphite, tocopherol and ester derivatives thereof such as tocopheryl acetate and tocopheryl linoleate, ascorbic acid and ester derivatives thereof, in particular ascorbyl esters of fatty acids such as ascorbyl palmitate, and butylated hydroxytoluene, and any mixture thereof.

51. The transdermal therapeutic system according to item 48,

wherein the penetration enhancer is selected from the group consisting of caprylic acid, glycerin, 2, 5-dimethylisosorbide ether, dimethylethyleneurea, N-diethyl-m-toluamide, polyethylene glycol, propylene glycol monocaprylate, 2-methoxy-4- (prop-2-en-1-yl) phenol, lactic acid, and laurocapram.

52. The transdermal therapeutic system according to any one of items 1 to 51,

the transdermal therapeutic system provides the following agomelatine skin permeation rates as measured in Franz diffusion cells with skin obtained with a dermatome

At 2 hours, 0.5. mu.g/cm²-hr to 15. mu.g/cm²-hr，

At 4 hours, 1. mu.g/cm²-hr to 20. mu.g/cm²-hr，

At 8 hours, 2. mu.g/cm²-hr to 25. mu.g/cm²-hr, and

at 16 hours, 1. mu.g/cm²-hr to 15. mu.g/cm²-hr。

53. The transdermal therapeutic system according to any one of items 1 to 52,

the transdermal therapeutic system provides the following cumulative permeation amounts of agomelatine at 8 hours as measured in a Franz diffusion cell with human skin obtained with a dermatome: at least 0.01mg/cm²At least 0.015mg/cm²Or at least 0.02mg/cm²Or less than or equal to 0.2mg/cm²Less than or equal to 0.15mg/cm²Or less than or equal to 0.1mg/cm²Or 0.01mg/cm²To 0.2mg/cm²、0.015mg/cm²To 0.15mg/cm²Or 0.02mg/cm²To 0.1mg/cm²。

54. The transdermal therapeutic system according to any one of items 1 to 53,

the transdermal therapeutic system provides the following agomelatine utilization after 8 hours as measured with the human skin obtained with a dermatome in a Franz diffusion cell: at least 10%, or at least 15%, or at least 20%.

55. The transdermal therapeutic system according to any one of items 1 to 54,

the transdermal therapeutic system also includes a release liner, an adhesive cover, or both.

56. The transdermal therapeutic system according to any one of items 1 to 55,

wherein the backing layer is substantially impermeable to agomelatine.

57. The transdermal therapeutic system of any one of clauses 1 to 56,

wherein the self-adhesive layer structure does not comprise an additional skin contact layer.

58. The transdermal therapeutic system according to any one of items 1 to 57,

wherein the self-adhesive layer structure consists of the backing layer and the agomelatine-containing layer.

59. The transdermal therapeutic system of any one of clauses 1 to 56,

wherein the self-adhesive layer structure comprises an additional skin contact layer.

60. The transdermal therapeutic system of any one of clauses 1-59, for use in a method of treatment.

61. The transdermal therapeutic system of item 60, for use in a method of treating major depression.

62. The transdermal therapeutic system according to clause 60 or 61, for use in a method of treatment,

wherein the transdermal therapeutic system is applied to the skin of a human patient and maintained on the skin for at least 2 hours, at least 4 hours, or at least 6 hours, or less than or equal to 24 hours, less than or equal to 18 hours, or less than or equal to 14 hours, or 2 to 24 hours, 4 to 18 hours, or 6 to 14 hours.

63. A method for treating a disease of the respiratory tract,

wherein the transdermal therapeutic system according to any one of the items 1 to 59 is applied to the skin of a human patient.

64. A method for the treatment of major depression,

65. According to the treatment method described in the item 63 or 64,

wherein the transdermal therapeutic system according to any one of items 1 to 61 is applied to the skin of a human patient and maintained on the skin for at least 2 hours, at least 4 hours, or at least 6 hours, or less than or equal to 24 hours, less than or equal to 18 hours, or less than or equal to 14 hours, or from 2 to 24 hours, from 4 to 18 hours, or from 6 to 14 hours.

66. A process for the manufacture of an agomelatine-containing layer, comprising the steps of:

67. In accordance with the method set forth in item 70,

wherein in step i) the agomelatine is dissolved or dispersed.

68. According to the method as described in the item 70 or 71,

wherein the solvent comprises an alcohol solvent selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof.

69. In accordance with the method set forth in item 72,

wherein the solvent comprises, or consists of, ethanol.

70. The method of any of items 66-69,

wherein the solvent comprises substantially no water.

71. The method of any of items 66-70,

wherein the solvent comprises less than 1 wt%, less than 0.5 wt%, or less than 0.1 wt% water.

72. The method of any of clauses 66-71,

wherein the drying is carried out at a temperature of 40 to 90 ℃, or 50 to 70 ℃.

73. The method of any of items 66-72,

wherein the crystallization inhibitor is polyvinylpyrrolidone, or

74. The method of any of items 66-73,

9 to 15, and preferably 10.2 to 13.8,

15 to 20, and preferably 15.3 to 18.4,

20 to 27, and preferably 22.5 to 27.0,

27 to 35, and preferably 27.0 to 32.4, and

75 to 110, and preferably 81.0 to 97.2.

75. According to the method of any of items 66-74,

wherein step i) consists of combining in a solvent at least agomelatine, a hydrophobic polymer, polyvinylpyrrolidone and a solubilizer selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of propylene glycol mono-and diesters of fatty acids, levulinic acid, polyethylene glycol ether and diethylene glycol monoethyl ether to obtain a coating composition.

76. The method of any of items 66-75,

77. The method of any of items 66-76,

78. In accordance with the method set forth in item 77,

79. In accordance with the method set forth in item 78,

80. According to the method as set forth in the item 79,

81. The method of any of clauses 77-80,

wherein the polysiloxane-based pressure-sensitive adhesive is characterized by a solution viscosity of greater than about 150mPa · s, or from about 200mPa · s to about 700mPa · s, at 25 ℃ and 60% solids in n-heptane, preferably as measured using a Brookfield RVT viscometer equipped with a rotor number 5 at 50rpm, or by a complex viscosity of less than about 1x10 at 0.01rad/s at 30 ℃⁹Poise, or about 1x10⁵To about 9x10⁸Poise.

82. The method of any of items 66-76,

wherein the hydrophobic polymer is polyisobutylene.

83. In accordance with the method set forth in item 82,

wherein the hydrophobic polymer is a polymer having a viscosity average molecular weight M of 1,110,000_v1,550,000, a weight average molecular weight M_wAnd an average molecular weight distribution M of 2.9_w/M_nOr a high molecular weight polyisobutylene having a viscosity average molecular weight M of 40,000_vWeight average molecular weight M of 53,000_wAnd an average molecular weight distribution M of 3.2_w/M_nOr a mixture thereof.

84. According to the method as set forth in item 83,

85. The method of any of items 66-76,

wherein the hydrophobic polymer is a styrene-isoprene-styrene block copolymer.

86. The method of any of items 66-76,

wherein the hydrophobic polymer is a silicone acrylic hybrid polymer.

87. According to the method of any of items 66-86,

wherein in step i) the agomelatine is combined in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, mixed form of any of the foregoing forms or a mixture thereof.

88. Transdermal therapeutic system for the transdermal administration of agomelatine, which is obtainable by the manufacturing process according to any one of items 66 to 87.

89. Transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i)2 to 6 wt% agomelatine;

ii) a hydrophobic polymer;

iii)2 to 7 wt% polyvinylpyrrolidone; and

wherein

90. Transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i)2 to 6 wt% agomelatine;

ii) a hydrophobic polymer; and

iii)7 to 15 wt% polyvinylpyrrolidone;

wherein

Claims

1. A transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, the self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i) agomelatine;

ii) a hydrophobic polymer; and

wherein

2. A transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, the self-adhesive layer structure comprising:

A) a backing layer; and

B) an agomelatine-containing layer comprising:

i) agomelatine; and

ii) a hydrophobic polymer;

wherein

the agomelatine-containing layer belongs to a microreservoir type.

3. Transdermal therapeutic system in accordance with claim 2,

wherein the agomelatine-containing layer further comprises a crystallization inhibitor, or comprises at least 1 wt% of a crystallization inhibitor, and/or

4. Transdermal therapeutic system in accordance with any one of claims 1 and 3,

wherein the agomelatine-containing layer comprises at least 1.5 wt%, at least 2.5 wt%, at least 4 wt%, or at least 5 wt% of the crystallization inhibitor, and/or

Wherein the crystallization inhibitor is polyvinylpyrrolidone, and/or

5. Transdermal therapeutic system in accordance with one of claims 1 to 4,

6. Transdermal therapeutic system in accordance with claim 5,

7. Transdermal therapeutic system in accordance with one of claims 1 to 6,

wherein the agomelatine-containing layer comprises a crystallization inhibitor and the total amount of crystallization inhibitor and solubilizer present in the agomelatine-containing layer is at least 2.5 wt.%, at least 3.5 wt.%, at least 4 wt.% or at least 5 wt.%, and/or

Wherein the ratio of the total amount of crystallization inhibitor and solubilizer present in the agomelatine-containing layer to the amount of agomelatine present in the agomelatine-containing layer is at least 1:2, at least 1:1, or at least 2:1, and/or

Wherein the agomelatine-containing layer comprises at least 0.5 wt% agomelatine, at least 1 wt% agomelatine, or at least 1.5 wt% agomelatine, or

Wherein the agomelatine-containing layer comprises 0.5 to less than or equal to 8 wt% agomelatine, 1 to less than or equal to 6 wt% agomelatine, or 1.5 to less than or equal to 5 wt% agomelatine, and/or

Wherein the agomelatine-containing layer comprises substantially no isopropanol, and/or

Wherein the agomelatine-containing layer does not comprise an acrylic polymer in an amount greater than 70 wt%, greater than 50 wt%, or greater than 30 wt% relative to the agomelatine-containing layer, and/or

Wherein the agomelatine-containing layer does not contain agomelatine crystals, and/or

8. Transdermal therapeutic system in accordance with one of claims 1 to 7,

wherein the hydrophobic polymer is a silicone-based pressure sensitive adhesive, and/or

Wherein the amount of the hydrophobic polymer is at least 75 wt%, at least 80 wt% or at least 75 wt%, or the amount of the hydrophobic polymer is less than or equal to 98 wt%, less than or equal to 94 wt% or less than or equal to 90 wt%, or the amount of the hydrophobic polymer is in the range of 75 to 98 wt%, 80 to 94 wt%, or 85 to 90 wt% relative to the agomelatine-containing layer.

9. Transdermal therapeutic system in accordance with one of claims 1 to 8,

wherein the agomelatine-containing layer is a dry biphasic layer having

b) an internal phase having a composition comprising the agomelatine,

wherein the inner phase forms dispersed deposits in the outer phase.

10. Transdermal therapeutic system in accordance with claim 9,

Wherein the pressure sensitive adhesive composition of the outer phase is substantially free of crystallization inhibitors, and/or

11. Transdermal therapeutic system in accordance with one of claims 1 to 10,

At 2 hours, 0.5. mu.g/cm²-hr to 15. mu.g/cm²-hr，

At 4 hours, 1. mu.g/cm²-hr to 20. mu.g/cm²-hr，

At 8 hours, 2. mu.g/cm²-hr to 25. mu.g/cm²-hr, and

at 16 hours, 1. mu.g/cm²-hr to 15. mu.g/cm²-hr，

And/or

12. Transdermal therapeutic system in accordance with any one of claims 1 to 11 for use in a method of treatment.

13. A method for treating a disease of the respiratory tract,

wherein the transdermal therapeutic system according to any one of claims 1 to 11 is applied to the skin of a human patient.

14. Transdermal therapeutic system according to claim 12 or therapeutic method according to claim 13,

wherein the method of treatment is a method of treating major depression, and/or

15. A method for manufacturing an agomelatine-containing layer, comprising the steps of:

iii) drying the applied coating composition to form the agomelatine-containing layer,

wherein

16. A transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, the self-adhesive layer structure comprising:

A) a backing layer;

and

B) an agomelatine-containing layer comprising:

i)2 to 6 wt% agomelatine;

ii) a hydrophobic polymer;

iii)2 to 7 wt% polyvinylpyrrolidone; and

or

B) An agomelatine-containing layer comprising:

i)2 to 6 wt% agomelatine;

ii) a hydrophobic polymer; and

iii)7 to 15 wt% polyvinylpyrrolidone;

wherein